Detoxification & Inter-Individual Variation

 
         
 

compiled by Teresa Binstock for
Generation Rescue
June 2008

Detoxification & Inter-Individual Variation

 

Introduction:  As numerous citations in this set of webpages make clear, AD, ADHD, and autism are associated with environmental pollutants (eg, 25-26, 32).

An important question arises. Why aren't all children affected similarly if they have similar exposures?  Not all individuals have the same ability to detoxify (eg, 2). Also, acquired pathologies can deplete nutrients needed for detoxification and for immunity (33). As a result, toxic exposures affect individuals differently. The phrase inter-individual variation refers to differences between people. The asbstracts hereinbelow provide a sketch of inter-individual variation as it affects detoxification of pollutants.

1. Human sulfotransferases and their role in chemical metabolism

Gamage N et al.
Toxicol Sci. 2006 Mar;90(1):5-22. Epub 2005 Dec 1.
http://toxsci.oxfordjournals.org/cgi/content/full/90/1/5

Sulfonation is an important reaction in the metabolism of numerous xenobiotics, drugs, and endogenous compounds. A supergene family of enzymes called sulfotransferases (SULTs) catalyze this reaction. In most cases, the addition of a sulfonate moiety to a compound increases its water solubility and decreases its biological activity. However, many of these enzymes are also capable of bioactivating procarcinogens to reactive electrophiles. In humans three SULT families, SULT1, SULT2, and SULT4, have been identified that contain at least thirteen distinct members. SULTs have a wide tissue distribution and act as a major detoxification enzyme system in adult and the developing human fetus. Nine crystal structures of human cytosolic SULTs have now been determined, and together with site-directed mutagenesis experiments and molecular modeling, we are now beginning to understand the factors that govern distinct but overlapping substrate specificities. These studies have also provided insight into the enzyme kinetics and inhibition characteristics of these enzymes. The regulation of human SULTs remains as one of the least explored areas of research in the field, though there have been some recent advances on the molecular transcription mechanism controlling the individual SULT promoters. Interindividual variation in sulfonation capacity may be important in determining an individual's response to xenobiotics, and recent studies have begun to suggest roles for SULT polymorphism in disease susceptibility. This review aims to provide a summary of our present understanding of the function of human cytosolic sulfotransferases.
PMID: 16322073


2. Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology

Bolt HM, Thier R.
Curr Drug Metab. 2006 Aug;7(6):613-28.

Although cytosolic glutathione S-transferase (GST) enzymes occupy a key position in biological detoxification processes, two of the most relevant human isoenzymes, GSTT1-1 and GSTM1-1, are genetically deleted (non-functional alleles GSTT1*0 and GSTM1*0) in a high percentage of the human population, with major ethnic differences. The structures of the GSTT and GSTM gene areas explain the underlying genetic processes. GSTT1-1 is highly conserved during evolution and plays a major role in phase-II biotransformation of a number of drugs and industrial chemicals, e.g. cytostatic drugs, hydrocarbons and halogenated hydrocarbons. GSTM1-1 is particularly relevant in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons. Several lines of evidence suggest that hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of reactive oxygen species that are likely to be involved in cellular processes of inflammation, ageing and degenerative diseases. There is cumulating evidence that combinations of the GSTM1*0 state with other genetic traits affecting the metabolism of carcinogens (CYP1A1, GSTP1) may predispose the aero-digestive tract and lung, especially in smokers, to a higher risk of cancer. The GSTM1*0 status appears also associated with a modest increase in the risk of bladder cancer, consistent with a GSTM1 interaction with carcinogenic tobacco smoke constituents. Both human GST deletions, although largely counterbalanced by overlapping substrate affinities within the GST superfamily, have consequences when the organism comes into contact with distinct man-made chemicals. This appears relevant in industrial toxicology and in drug metabolism.
PMID: 16918316


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3. Glutathione transferases

Hayes JD, Flanagan JU, Jowsey IR.
Annu Rev Pharmacol Toxicol. 2005;45:51-88.

This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous alpha,beta-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-kappaB (NF-kappaB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.
PMID: 15822171


4. Glutathione

Jefferies H et al.
ANZ J Surg. 2003 Jul;73(7):517-22.

Glutathione (GSH) is an ubiquitous thiol-containing tripeptide that plays a key role in cell biology. It modulates cell response to redox changes associated with the reactive oxygen species, detoxifies the metabolites of drugs; regulates gene expression and apoptosis, and is involved in the transmembrane transport of organic solutes. Polymorphism has been observed in key enzymes of GSH metabolism and some alleles have been associated with an impaired redox buffer system downsteam diseases, and susceptibility to ischaemia. These varied activities make GSH an attractive target for a more reductionist approach to the prevention and management of many conditions of interest to surgeons.
PMID: 12864828


5. Glutathione S-transferase polymorphisms and their biological consequences

Hayes JD, Strange RC.
Pharmacology. 2000 Sep;61(3):154-66.

Two supergene families encode proteins with glutathione S-transferase (GST) activity: the family of soluble enzymes comprises at least 16 genes; the separate family of microsomal enzymes comprises at least 6 genes. These two GST families are believed to exert a critical role in cellular protection against oxidative stress and toxic foreign chemicals. They detoxify a variety of electrophilic compounds, including oxidized lipid, DNA and catechol products generated by reactive oxygen species-induced damage to intracellular molecules. An increasing number of GST genes are being recognized as polymorphic. Certain alleles, particularly those that confer impaired catalytic activity (e.g. GSTM1(*)0, GSTT1(*)0), may be associated with increased sensitivity to toxic compounds. GST polymorphisms may be disease modifying; for example, in subgroups of patients with basal cell carcinoma or bronchial hyper-responsiveness, certain GST appear to exert a statistically significant and biologically relevant impact on disease susceptibility. Copyright 2000 S. Karger AG, Basel
PMID: 10971201


6. Glutathione-S-transferase family of enzymes

Strange RC et al.
Mutat Res. 2001 Oct 1;482(1-2):21-6.

The loci encoding the glutathione-S-transferase (GST) enzymes comprise a large supergene family located on at least seven chromosomes. The function of the GST enzymes has traditionally been considered to be the detoxication of electrophiles by glutathione conjugation. A wide variety of endogenous (e.g. by-products of reactive oxygen species activity) and exogenous (e.g. polycyclic aromatic hydrocarbons) electrophilic substrates have been identified. Interestingly, recent data has suggested a role, at least for the pi class gene product, in jun kinase inhibition. Since many GST genes are polymorphic, there has been considerable interest in determining whether particular allelic variants are associated with altered risk (or outcome) of a variety of diseases...


7. Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity

Wormhoudt LW, Commandeur JN, Vermeulen NP.
Crit Rev Toxicol. 1999 Jan;29(1):59-124.

In this review, an overview is presented of the current knowledge of genetic polymorphisms of four of the most important enzyme families involved in the metabolism of xenobiotics, that is, the N-acetyltransferase (NAT), cytochrome P450 (P450), glutathione-S-transferase (GST), and microsomal epoxide hydrolase (mEH) enzymes. The emphasis is on two main topics, the molecular genetics of the polymorphisms and the consequences for xenobiotic metabolism and toxicity. Studies are described in which wild-type and mutant alleles of biotransformation enzymes have been expressed in heterologous systems to study the molecular genetics and the metabolism and pharmacological or toxicological effects of xenobiotics. Furthermore, studies are described that have investigated the effects of genetic polymorphisms of biotransformation enzymes on the metabolism of drugs in humans and on the metabolism of genotoxic compounds in vivo as well. The effects of the polymorphisms are highly dependent on the enzyme systems involved and the compounds being metabolized. Several polymorphisms are described that also clearly influence the metabolism and effects of drugs and toxic compounds, in vivo in humans. Future perspectives in studies on genetic polymorphisms of biotransformation enzymes are also discussed. It is concluded that genetic polymorphisms of biotransformation enzymes are in a number of cases a major factor involved in the interindividual variability in xenobiotic metabolism and toxicity. This may lead to interindividual variability in efficacy of drugs and disease susceptibility.
PMID: 10066160


8. Effect of glutathione S-transferase M1 polymorphisms on biomarkers of exposure and effects

Srám RJ.
Environ Health Perspect. 1998 Feb;106 Suppl 1:231-9.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1533289&blobtype=pdf

Genotypes responsible for interindividual differences in ability to activate or detoxify genotoxic agents are recognized as biomarkers of susceptibility. Among the most studied genotypes are human glutathione transferases. The relationship of genetic susceptibility to biomarkers of exposure and effects was studied especially in relation to the genetic polymorphism of glutathione S-transferase M1 (GSTM1). For this review papers reporting the effect of GSTM1 genotype on DNA adducts, protein adducts, urine mutagenicity, Comet assay parameters, chromosomal aberrations, sister chromatid exchanges (SCE), micronuclei, and hypoxanthine-guanine phosphoribosyl transferase mutations were assessed...  The relationship between genotypes and biomarkers of exposure and effects may provide an important guide to the risk assessment of human exposure to mutagens and carcinogens.
PMID: 9539016


9. Diet, genetic polymorphisms, detoxification, and health risks

Lampe JW.
Altern Ther Health Med. 2007 Mar-Apr;13(2):S108-11.

Modulation of detoxification enzymes is one mechanism by which diet may influence risk of cancer and other diseases. However, genetic differences in taste preference, food tolerance, nutrient absorption, and metabolism and response of target tissues all potentially influence the effect of diet on disease risk. Thus, disease prevention at the individual and population level needs to be evaluated in the context of the totality of genetic background and exposures to both causative agents and chemopreventive compounds. Polymorphisms in the detoxification enzymes that alter protein expression and/or function can modify risk in individuals exposed to the relevant substrates. Diet is a mixture of carcinogens, mutagens, and protective agents that are all metabolized by detoxification enzymes. Genotypes associated with more favorable handling of carcinogens may be associated with less favorable handling of phytochemicals. For example, glutathione S-transferases (GST) detoxify polycyclic aromatic hydrocarbons present in grilled meats. GSTs also conjugate isothiocyanates, the chemopreventive compounds found in cruciferous vegetables. Polymorphisms in the GSTM1 and GSTT1 genes result in complete lack of GSTM1-1 and GSTT1-1 proteins, respectively. In some observational studies of cancer, cruciferous vegetable intake confers greater protection in individuals with these polymorphisms; however, in other studies, the converse is observed. A recent study of sulforaphane pharmacokinetics suggests that lack of the GSTM1 enzyme is associated with more rapid excretion of sulforaphane. Many phytochemicals are also conjugated with glucuronide and sulfate moieties, and are excreted in urine and bile. Polymorphisms in UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT) may contribute to the variability in phytochemical clearance and efficacy. The effects of UGT polymorphisms on flavonoid clearance have not been examined, but UGT polymorphisms affect glucuronidation of several drugs and steroid hormones. Genetic polymorphisms in detoxification enzymes may account in part for individual variation in disease risk but have to be considered in the context of other aspects of human genetics, gut bacterial genetics, and environmental exposures.
PMID: 17405687


10. Polyphenols and glutathione synthesis regulation

Moskaug JØ, Carlsen H, Myhrstad MC, Blomhoff R.
Am J Clin Nutr. 2005 Jan;81(1 Suppl):277S-283S.
http://www.ajcn.org/cgi/content/full/81/1/277S

Polyphenols in food plants are a versatile group of phytochemicals with many potentially beneficial activities in terms of disease prevention... Evidently, glutathione is important in many diseases, and regulation of intracellular glutathione concentrations may be one mechanism by which diet influences disease development. The aim of this review is to discuss some of the mechanisms involved in the glutathione-mediated, endogenous, cellular antioxidant defense system, how its possible modulation by dietary polyphenols such as flavonoids may influence disease development, and how it can be studied with in vivo imaging.
PMID: 15640491


11. Inborn errors in the metabolism of glutathione

Ristoff E, Larsson A.
Orphanet J Rare Dis. 2007 Mar 30;2:16.
http://www.ojrd.com/content/2/1/16

Glutathione is a tripeptide composed of glutamate, cysteine and glycine. Glutathione is present in millimolar concentrations in most mammalian cells and it is involved in several fundamental biological functions, including free radical scavenging, detoxification of xenobiotics and carcinogens, redox reactions, biosynthesis of DNA, proteins and leukotrienes, as well as neurotransmission/neuromodulation. Glutathione is metabolised via the gamma-glutamyl cycle, which is catalyzed by six enzymes. In man, hereditary deficiencies have been found in five of the six enzymes. Glutathione synthetase deficiency is the most frequently recognized disorder and, in its severe form, it is associated with hemolytic anemia, metabolic acidosis, 5-oxoprolinuria, central nervous system (CNS) damage and recurrent bacterial infections. Gamma-glutamylcysteine synthetase deficiency is also associated with hemolytic anemia, and some patients with this disorder show defects of neuromuscular function and generalized aminoaciduria. Gamma-glutamyl transpeptidase deficiency has been found in patients with CNS involvement and glutathionuria. 5-Oxoprolinase deficiency is associated with 5-oxoprolinuria but without a clear association with other symptoms. Dipeptidase deficiency has been described in one patient. All disorders are very rare and inherited in an autosomal recessive manner. Most of the mutations are leaky so that many patients have residual enzyme activity. Diagnosis is made by measuring the concentration of different metabolites in the gamma-glutamyl cycle, enzyme activity and in glutathione synthetase and gamma-glutamylcysteine synthetase deficiency, also by mutation analysis. Prenatal diagnosis has been preformed in glutathione synthetase deficiency. The prognosis is difficult to predict, as few patients are known, but seems to vary significantly between different patients. The aims of the treatment of glutathione synthesis defects are to avoid hemolytic crises and to increase the defense against reactive oxygen species. No treatment has been recommended for gamma-glutamyl transpeptidase, 5-oxoprolinase and dipeptidase deficiency.
PMID: 17397529


12. Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization

Westphal GA et al.
Int Arch Occup Environ Health. 2000 Aug;73(6):384-8.

OBJECTIVE: Thimerosal is an important preservative in vaccines and ophthalmologic preparations. The substance is known to be a type IV sensitizing agent. High sensitization rates were observed in contact-allergic patients and in health care workers who had been exposed to thimerosal-preserved vaccines. There is evidence for the involvement of the glutathione system in the metabolism of thimerosal or its decomposition products (organomercury alkyl compounds). Thus detoxification by polymorphically expressed glutathione S-transferases such as GSTT1 and GSTM1 might have a protective effect against sensitization by these substances. METHODS: To address this question, a case control study was conducted, including 91 Central European individuals with a positive patch-test reaction to thimerosal. This population was compared with 169 healthy controls and additionally with 114 individuals affected by an allergy against para-substituted aryl compounds. The latter population was included in order to test whether possible associations were due to substance-specific effects, or were a general feature connected with type IV immunological diseases. Homozygous deletions of GSTT1 and GSTM1 were determined by polymerase chain reaction. RESULTS: Glutathione S-transferase M1 deficiency was significantly more frequent among patients sensitized to thimerosal (65.9%, P = 0.013) compared with the healthy control group (49.1%) and the "para-compound" group (48%, P = 0.034). Glutathione S-transferase T1 deficiency in the thimerosal/mercury group (19.8%) was barely elevated versus healthy controls (16.0%) and the "para-compound" group (14.0%). The combined deletion (GSTT1-/GSTM1-) was markedly more frequent among thimerosal-sensitized patients than in healthy controls (17.6% vs. 6.5%, P = 0.0093) and in the "para-compound" group (17.6% vs. 6.1%, P =0.014), revealing a synergistic effect of these enzyme deficiencies (healthy controls vs. thimerosal GSTM1 negative individuals, OR = 2.0 [CI = 1.2-3.4], GSTT1-, OR = 1.2 [CI = 0.70-2.1], GSTM1/T1-, OR = 3.1 [CI = 1.4-6.5]). CONCLUSIONS: Since the glutathione-dependent system was repeatedly shown to be involved in the metabolism of thimerosal decomposition products, the observed association may be of functional relevance.
PMID: 11007341


13. Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal

Müller M et al.
Int J Hyg Environ Health. 2001 Jul;203(5-6):479-81.

We have investigated the interaction of thimerosal, a widely used antiseptic and preservative, with the human erythrocytic GST T1 (glutathione-S-transferase T1). This detoxifying enzyme is expressed in the erythrocytes of solely the human species and it displays a genetic polymorphism. Due to this polymorphism about 25% of the individuals of the caucasian population lack this activity ("non-conjugators"), while 75% show it ("conjugators") (Hallier, E., et al., 1993). Using our newly developed HPLC-fluorescence detection assay (Müller, M., et al., 2001) we have profiled the kinetics of enzyme inhibition in erythrocyte lysates of two individuals previously identified as "normal conjugator" (medium enzyme activity) and "super-conjugator" (very high activity). For the normal conjugator we have determined a 2.77 mM thimerosal concentration to inhibit 50% of the GST T1 activity. In the case of the super-conjugator a 2.3 mM thimerosal concentration causes a 50% inhibition of the enzyme activity. For both phenotypes a 14.8 mM thimerosal concentration results in residual enzyme activities equal to those typically detected in non-conjugator lysates. Thus, sufficiently high doses of thimerosal may be able to change the phenotypic status of an individual--at least in vitro--by inhibition of the GST T1 enzyme.
PMID: 11556154


15. Thimerosal induces micronuclei in the cytochalasin B block micronucleus test with human lymphocytes

Westphal GA et al.
 Arch Toxicol. 2003 Jan;77(1):50-5.

Thimerosal is a widely used preservative in health care products, especially in vaccines. Due to possible adverse health effects, investigations on its metabolism and toxicity are urgently needed. An in vivo study on chronic toxicity of thimerosal in rats was inconclusive and reports on genotoxic effects in various in vitro systems were contradictory. Therefore, we reinvestigated thimerosal in the cytochalasin B block micronucleus test. Glutathione S-transferases were proposed to be involved in the detoxification of thimerosal or its decomposition products. Since the outcome of genotoxicity studies can be dependent on the metabolic competence of the cells used, we were additionally interested whether polymorphisms of glutathione S-transferases (GSTM1, GSTT1, or GSTP1) may influence the results of the micronucleus test with primary human lymphocytes. Blood samples of six healthy donors of different glutathione S-transferase genotypes were included in the study. At least two independent experiments were performed for each blood donor. Significant induction of micronuclei was seen at concentrations between 0.05-0.5 micro g/ml in 14 out of 16 experiments. Thus, genotoxic effects were seen even at concentrations which can occur at the injection site. Toxicity and toxicity-related elevation of micronuclei was seen at and above 0.6 micro g/ml thimerosal. Marked individual and intraindividual variations in the in vitro response to thimerosal among the different blood donors occurred. However, there was no association observed with any of the glutathione S-transferase polymorphism investigated. In conclusion, thimerosal is genotoxic in the cytochalasin B block micronucleus test with human lymphocytes. These data raise some concern on the widespread use of thimerosal.
PMID: 12491041


16. Population genetic approaches to neurological disease: Parkinson's disease as an example

Gandhi S et al.
Philos Trans R Soc Lond B Biol Sci. 2005 Aug 29;360(1460):1573-8.
http://journals.royalsociety.org/content/4emfvuqyahuexwcb/

Parkinson's disease (PD) is a common, progressive, incurable disabling condition. The cause is unknown but over the past few years tremendous progress in our understanding of the genetic bases of this condition has been made. To date, this has almost exclusively come from the study of relatively rare Mendelian forms of the disease and there are no currently, widely accepted common variants known to increase susceptibility.The role that the "Mendelian" genes play in common sporadic forms of PD is unknown. Moreover, most studies in PD can really be described as candidate polymorphism studies rather than true and complete assessments of the genes themselves. We provide a model of how one might tackle some of these issues using Parkinson's disease as an illustration. One of the emerging hypotheses of gene environment interaction in Parkinson's disease is based on drug metabolizing (or xenobiotic) enzymes and their interaction with putative environmental toxins. This motivated us to describe a tagging approach for an extensive but not exhaustive list of 55 drug metabolizing enzyme genes. We use these data to illustrate the power, and some of the limitations of a haplotype tagging approach. We show that haplotype tagging is extremely efficient and works well with only a modest increase in effort through different populations. The tagging approach works much less well if the minor allele frequency is below 5%. However, it will now be possible using these tags to evaluate these genes comprehensively in PD and other neurodegenerative conditions.
PMID: 16096106


17. The nuclear pregnane X receptor regulates xenobiotic detoxification

Kliewer SA.
J Nutr. 2003 Jul;133(7 Suppl):2444S-2447S.
http://jn.nutrition.org/cgi/content/full/133/7/2444S

The pregnane X receptor (PXR), which is a member of the nuclear receptor family of ligand-activated transcription factors, is an integral component of the body's defense mechanism against toxic xenobiotics. PXR is activated by a broad spectrum of lipophilic xenobiotics including prescription drugs, herbs, pesticides, endocrine disruptors and other environmental contaminants. The promiscuous ligand-binding properties of PXR are facilitated by the large volume and smooth shape of its ligand-binding pocket. PXR binds to DNA as a heterodimer with the 9-cis retinoic acid receptor (RXR) and regulates a large number of genes involved in the detoxification and excretion of toxic substances. Although PXR evolved to protect the body, its activation by various prescription drugs and herbs such as St. John's wort represents the molecular basis for an important class of drug-drug interactions. Assays that detect PXR activation can now be used to predict and prevent these drug-drug interactions.
PMID: 12840222


18. Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals

Sato M, Kondoh M.
Tohoku J Exp Med. 2002 Jan;196(1):9-22.
http://www.jstage.jst.go.jp/article/tjem/196/1/196_9/_article

Metallothionein (MT) is a ubiquitous, cysteine-rich, metal-binding protein. MT synthesis is induced by various stimuli such as cadmium, mercury, zinc, oxidative stress, glucocorticoid, and anticancer agents. Recently, transgenic mice with loss-of-function mutations in the MT-I/-II genes were established. It has been assumed that MT plays a role in the detoxification of heavy metals. In recent studies using MT-null mice, the ability of MT to protect against cadmium-induced renal, liver and bone injuries has been confirmed. Moreover, MT is also capable of scavenging oxygen free radicals. MT is involved in the protection of tissues against various forms of oxidative injury, including radiation, lipid peroxidation, oxidative stress caused by anticancer drugs, and conditions of hyperoxia. However, MT still lacks an established biological function. Unexpectedly, the MT-null mice were apparently in good health, and the critical biological roles of MT have been questioned. MT seems to be a protective protein produced in response to a variety of stresses. Here, current studies on the protective roles of MT against toxicity of heavy metals and reactive oxygen species are reviewed, and the putative biological functions of MT are discussed.
PMID: 12498322


19. Sulfation through the looking glass--recent advances in sulfotransferase research for the curious

Coughtrie MW.
Pharmacogenomics J. 2002;2(5):297-308. [email protected]
http://www.nature.com/tpj/journal/v2/n5/full/6500117a.html

Members of the cytosolic sulfotransferase (SULT) superfamily catalyse the sulfation of a multitude of xenobiotics, hormones and neurotransmitters. Humans have at least 10 functional SULT genes, and a number of recent advances reviewed here have furthered our understanding of SULT function. Analysis of expression patterns has shown that sulfotransferases are highly expressed in the fetus, and SULTs may in fact be a major detoxification enzyme system in the developing human. The X-ray crystal structures of three SULTs have been solved and combined with mutagenesis experiments and molecular modelling, they have provided the first clues as to the factors that govern the unique substrate specificities of some of these enzymes. In the future these and other studies will facilitate prediction of the fate of chemicals metabolised by sulfation. Variation in sulfation capacity may be important in determining an individual's response to xenobiotics, and there has been an explosion in information on sulfotransferase polymorphisms and their functional consequences, including the influence of SULT1A1 genotype on susceptibility to colorectal and breast cancer. Finally, the first gene knockout experiments with SULTs have recently been described, with the generation of estrogen sulfotransferase deficient mice in which reproductive capacity is compromised. Our improved understanding of these enzymes will have significant benefits in such diverse areas as drug design and development, cancer susceptibility, reproduction and development.
PMID: 12439736


20. Transport of glutathione-conjugates in human erythrocytes

Sharma R, Awasthi S, Zimniak P, Awasthi YC.
Acta Biochim Pol. 2000;47(3):751-62.
http://www.actabp.pl/pdf/3_2000/751.pdf

The last step of detoxification of both endogenous and environmental toxicants is typically a conjugation that produces a bulky hydrophilic molecule. The excretion of such conjugates out of cells is of sufficient biological importance to have led to the evolution of ATP-driven export pumps for this purpose. The substrate specificity of such transporters is broad, and in some cases it has been shown to include not only anionic conjugates but also neutral or weakly cationic drugs. In the present article, we review the molecular identity, functional and structural characteristics of these pumps, mainly on the example of human erythrocytes, and discuss their physiological role in detoxification and in the multidrug resistance phenotype of cancer cells.
PMID: 11310974


21. Metabolism of chemical carcinogens

Guengerich FP.
Carcinogenesis. 2000 Mar;21(3):345-51.
http://carcin.oxfordjournals.org/cgi/content/full/21/3/345

The transformation of chemicals is important in carcinogenesis, both in bioactivation and detoxification. Major advances in the past 20 years include appreciation of the migration of reactive electrophiles, the ability of Phase II conjugating enzymes to activate chemicals, understanding of the human enzymes, the realization that DNA modification can result from endogenous chemicals, and the demonstration that cancers can result from the metabolism of chemicals to non-covalently bound products. Pathways of transformation in which major insight was gained during the past 20 years include nitropolycyclic hydrocarbons, polycyclic hydrocarbons and their diols, vinyl halides and dihaloalkanes. Advances in analytical methods and recombinant DNA technology contributed greatly to the study of metabolism of chemical carcinogens. Major advances have been made in the assignment of roles of individual enzymes in reactions. The knowledge developed in this field has contributed to growth in the areas of chemoprevention, molecular epidemiology and species comparisons of risk. Some of the areas in which future development relevant to carcinogen metabolism is expected involve pathways of transformation of certain chemicals, regulation of genes coding for many of the enzymes under consideration and genomics.
PMID: 10688854


22. The detoxification enzyme systems

Liska DJ.
Altern Med Rev. 1998 Jun;3(3):187-98.
http://www.thorne.com/media/detoxificationenzymes.pdf

The human body is exposed to a wide array of xenobiotics in one s lifetime, from food components to environmental toxins to pharmaceuticals, and has developed complex enzymatic mechanisms to detoxify these substances. These mechanisms exhibit significant individual variability, and are affected by environment, lifestyle, and genetic influences. The scientific literature suggests an association between impaired detoxification and certain diseases, including cancer, Parkinson's disease, fibromyalgia, and chronic fatigue/immune dysfunction syndrome. Data regarding these hepatic detoxification enzyme systems and the body s mechanisms of regulating them suggests the ability to efficiently detoxify and remove xenobiotics can affect these and other chronic disease processes. This article reviews the myriad detoxification enzyme systems, their regulatory mechanisms, and the dietary, lifestyle, and genetic factors influencing their activities, as well as laboratory tests available to assess their functioning.
PMID: 9630736


23. Advances in mechanisms of activation and deactivation of environmental chemicals

Goldstein JA, Faletto MB.
Environ Health Perspect. 1993 Apr;100:169-76.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1519589&blobtype=pdf

Environmental chemicals are both activated and detoxified by phase I and phase II enzymes. The principal enzymes involved in phase I reactions are the cytochrome P-450s. The phase II enzymes include hydrolase and the conjugative enzymes such as glucuronyltransferases, glutathione transferases, N-acetyltransferase, and sulfotransferase. Although other phase I and phase II enzymes exist, the present review is limited to these enzymes. Once thought to be a single enzyme, multiple cytochrome P-450 enzymes have been purified and characterized from many different species across the evolutionary tree. The application of molecular biology techniques to this field has identified more than 150 cytochrome P-450 genes to date. At least 20-30 cytochrome P-450 enzymes appear to exist in each mammalian species, and many polymorphisms in these enzymes are being identified. The cytochrome P-450 enzymes can now be expressed in recombinant form using cDNA expression systems. The phase II conjugative enzymes add a hydrophilic moiety such as sulfate, glucuronide, or acetate to compounds, which increases their water solubility and facilitates their excretion. However, conjugates of a number of compounds also result in more reactive electrophilic species, which appear to be the ultimate carcinogens. Many of these phase II enzymes also represent families of enzymes, and polymorphisms can affect the ability of these enzymes to metabolize chemicals. Whenever possible, we have reviewed knowledge of the human enzymes involved in particular pathways.
PMID: 8354165

24. The relevance of xenobiotic metabolism in the interindividual susceptibility to chemicals

Testai E.
Folia Histochem Cytobiol. 2001;39 Suppl 2:48-9.

Biotransformation enzymes may catalyze either detoxication or bioactivation reactions; indeed, many xenobiotics exert their toxic effects after metabolic activation to electrophilic chemicals, interacting with nucleophilic sites on cellular macromolecules. On the other hand, by increasing xenobiotic hydrophilicity, the drug-metabolizing enzymes favors excretion of lipophilic chemicals, not allowing their bioaccumulation up to toxic levels. The expression of the enzymes of the drug-metabolizing system is modulated by genetic, pathological, developmental, environmental and dietary factors. Genetic polymorphism resulting in interindividual and interethnic variation in xenobiotic metabolism is responsible for differences in the susceptibility to chemical-induced toxicity and carcinogenicity, allowing the identification of people at increased risk. Moreover, differences in drug metabolism may correspond to variability in drug response during pharmacological therapy, which can be manifest either as adverse reactions or as a lack of benefit.
PMID: 11820624


25. ADHD: Genes and Environment

26. AD & ADHD: Mercury, Lead, Aluminum, and other Pollutants

27. Pediatric pharmacokinetic data: implications for environmental risk assessment for children

Ginsberg G et al.
Pediatrics. 2004 Apr;113(4 Suppl):973-83.
http://pediatrics.aappublications.org/cgi/content/full/113/4/S1/973

Pharmacology and toxicology share a common interest in pharmacokinetic data, especially as it is available in pediatric populations. These data have been critical to the clinical pharmacologist for many years in designing age-specific dosing regimens. Now they are being used increasingly by toxicologists to understand the ontogeny of physiologic parameters that may affect the metabolism and clearance of environmental toxicants. This article reviews a wide range of physiologic and metabolic factors that are present in utero and in early postnatal life and that can affect the internal dose of an absorbed chemical and its metabolites. It also presents a child/adult pharmacokinetic database that includes data for 45 therapeutic drugs organized into specific children's age groupings and clearance pathways. Analysis of these data suggests that substantial child/adult differences in metabolism and clearance are likely for a variety of drugs and environmental chemicals in the early postnatal period. These results are also relevant to in utero exposures, where metabolic systems are even more immature, but exposures are greatly modified by the maternal system and placental metabolism. The implications of these child/adult differences for assessing children's risks from environmental toxicants is discussed with special focus on physiologically based pharmacokinetic modeling strategies that could simulate children's abilities to metabolize and eliminate chemicals at various developmental stages.
PMID: 15060190


28. Human interindividual variability in susceptibility to airborne particles

Hattis D et al.
Risk Anal. 2001 Aug;21(4):585-99.

Part of the explanation for the persistent epidemiological findings of associations between mortality and morbidity with relatively modest ambient exposures to airborne particles may be that some people are much more susceptible to particle-induced responses than others. This study assembled a database of quantitative observations of interindividual variability in pharmacokinetic and pharmacodynamic parameters likely to affect particle response. The pharmacodynamic responses studied included data drawn from epidemiologic studies of doses of methacholine, flour dust, and other agents that induce acute changes in lung function. In general, the amount of interindividual variability in several of these pharmacodynamic response parameters was greater than the variability in pharmacokinetic (breathing rate, deposition, and clearance) parameters. Quantitatively the results indicated that human interindividual variability of breathing rates and major pharmacokinetic parameters-total deposition and tracheobronchial clearance-were in the region of Log(GSD) = 0.1 to 0.2 (corresponding to geometric standard deviations of 10(.1)-10(.2) or 1.26-1.58). Deposition to the deep lung (alveolar region) appeared to be somewhat more variable: Log(GSD) of about 0.3 (GSD of about 2). Among pharmacodynamic parameters, changes in FEV1 in response to ozone and metabisulfite (an agent that is said to act primarily on neural receptors in the lung) were in the region of Log(GSD) of 0.2 to 0.4. However, similar responses to methacholine, an agent that acts on smooth muscle, seemed to have still more variability (0.4 to somewhat over 1.0, depending on the type of population studied). Similarly high values were suggested for particulate allergens. Central estimates of this kind of variability, and the close correspondence of the data to lognormal distributions, indicate that 99.9th percentile individuals are likely to respond at doses that are 150 to 450-fold less than would be needed in median individuals. It seems plausible that acute responses with this amount of variability could form part of the mechanistic basis for epidemiological observations of enhanced mortality in relation to ambient exposures to fine particles.
PMID: 11726014


29. Distributions of individual susceptibility among humans for toxic effects. How much protection does the traditional tenfold factor provide for what fraction of which kinds of chemicals and effects?

Hattis D, Banati P, Goble R.
Ann N Y Acad Sci. 1999;895:286-316.

A significant data base has been assembled on human variability in parameters representing a series of steps in the pathway from external exposure to the production of biological responses: contact rate (e.g., breathing rates/body weight, fish consumption/body weight); uptake or absorption (mg/kg)/intake or contact rate; general systemic availability net of first pass elimination and dilution; systemic elimination or half-life; active site availability/general systemic availability; physiological parameter change/active site availability; functional reserve capacity--change in baseline physiological parameter needed to pass a criterion of abnormal function or exhibit a response. This paper discusses the current results of analyzing these data to derive estimates for distributions of human susceptibility to different routes of exposure and types of adverse effects. The degree of protection is tentatively evaluated by projecting the incidences of effects that would be expected for a tenfold lowering of exposure from a 5% incidence level if the population distribution of susceptibility were truly log-normal out to the extreme tails, and if the populations, chemicals, and responses that gave rise to the underlying data were representative of the cases to which traditional uncertainty factor is applied. The results indicate that, acting by itself, a tenfold reduction in dose from a 5% effect level is associated with effect incidences ranging from slightly less than one in ten thousand, for a median chemical/response, to a few per thousand, for chemicals and responses that have greater human interindividual variability than 19 out of 20 typical chemicals/responses. In practice, for many of the cases where the traditional tenfold factor is applied, additional protection is provided by other uncertainty factors. Nevertheless, the results generate some reason for concern that current application of traditional safety or uncertainty factor approaches may allow appreciable incidences of responses in some cases.
PMID: 10676424


30. The economic impact of early life environmental tobacco smoke exposure: early intervention for developmental delay

Miller T et al.
Environ Health Perspect. 2006 Oct;114(10):1585-8.
http://www.ehponline.org/members/2006/9165/9165.html

BACKGROUND AND OBJECTIVES: Early-life exposure to environmental tobacco smoke (ETS) can result in developmental delay as well as childhood asthma and increased risk of cancer. The high cost of childhood asthma related to ETS exposure has been widely recognized; however, the economic impact of ETS-related developmental delay has been less well understood. METHODS AND RESULTS: The Columbia Center for Children's Environmental Health (CCCEH) has reported adverse effects of prenatal ETS exposure on child development in a cohort of minority women and children in New York City (odds ratio of developmental delay = 2.36; 95% confidence interval 1.22-4.58). Using the environmentally attributable fraction (EAF) approach, we estimated the annual cost of one aspect of ETS-related developmental delay: Early Intervention Services. The estimated cost of these services per year due to ETS exposure is > Dollars 50 million per year for New York City Medicaid births and Dollars 99 million per year for all New York City births. CONCLUSION: The high annual cost of just one aspect of developmental delay due to prenatal exposure to ETS provides further impetus for increased prevention efforts such as educational programs to promote smoke-free homes, additional cigarette taxes, and subsidizing of smoking cessation programs.
PMID: 17035147


31. Assessing cumulative health risks from exposure to environmental mixtures - three fundamental questions

Sexton K, Hattis D.
Environ Health Perspect. 2007 May;115(5):825-32. Epub 2007 Jan 24.
http://www.ehponline.org/members/2006/9165/9165.html

Differential exposure to mixtures of environmental agents, including biological, chemical, physical, and psychosocial stressors, can contribute to increased vulnerability of human populations and ecologic systems. Cumulative risk assessment is a tool for organizing and analyzing information to evaluate the probability and seriousness of harmful effects caused by either simultaneous and/or sequential exposure to multiple environmental stressors. In this article we focus on elucidating key challenges that must be addressed to determine whether and to what degree differential exposure to environmental mixtures contributes to increased vulnerability of exposed populations. In particular, the emphasis is on examining three fundamental and interrelated questions that must be addressed as part of the process to assess cumulative risk: a) Which mixtures are most important from a public health perspective? and b) What is the nature (i.e., duration, frequency, timing) and magnitude (i.e., exposure concentration and dose) of relevant cumulative exposures for the population of interest? c) What is the mechanism (e.g., toxicokinetic or toxicodynamic) and consequence (e.g., additive, less than additive, more than additive) of the mixture's interactive effects on exposed populations? The focus is primarily on human health effects from chemical mixtures, and the goal is to reinforce the need for improved assessment of cumulative exposure and better understanding of the biological mechanisms that determine toxicologic interactions among mixture constituents.
PMID: 17520074


32. Pollutants and autism:

 
33. Autism, Pollution, and Nutrients: a Unifying Relationship: Commentary by Teresa Binstock

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