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Gene-environment interaction in occupational toxicology
Symposium 7. Genetic Susceptibility in Occupational Toxicology in order to design and validate molecular epidemiology studies to investigate cancer susceptibility in humans and to develop rodent bioassays that accurately predict chemicals that might be human carcinogens. To address the role of P450s in whole animal carcinogenesis, mice were produced that lack the P450s known to catalyze carcinogen activation. Mouse lines having disrupted genes encoding P450s CYP IA2 (activates arylamines and heterocyclic amines), CYP2El (activates low Mr nitrosamines, benzene, vinyl chloride and other suspect carcinogens) and CYP lB l (activates polycyclic aromatic hydrocarbons) were established. These mice exhibit no grossly abnormal phenotypes, suggesting that the xenobiotic-metabolizing P450s have no critical roles in mammalian development and physiological homeostasis. However, the P450-null mice do show differences in sensitivities to acute chemical toxicity's thus establishing the importance of these enzymes in activation pathways that lead to cell death. Cancer bioassays, using the null mice, will establish their roles in carcinogenesis.
S7. Genetic Susceptibility in Occupational Toxicology
IS7/L1 I
GENE-ENVIRONMENT INTERACTION IN OCCUPATIONAL TOXICOLOGY
H. Vainio. International Agency for Research on Cancer, Lyon,
France Occupational chemicals are metabolized through a variety of enzymes, the regulation of which is complex. Common variations (' polymorphisms') in gene sequence can result in altered protein, which may have functional consequences. Since polyrnorphisms evolve over time in populations, ethnic differences in the prevalence of variants are often observed. The results of this work on polymorphic metabolic genes have yet to explain consistent differences in risk that theory might predict. Observed differences in risk between high- and low-risk genotypes are typically threefold or less. If genetic host factors modify the carcinogenic and toxic effects of many: chemical hazards, their role appears to be particularly important in that subset of health effects that are more clearly ' idiosyncratic' : effects seen at low dose among a small fraction of individuals but only at far higher doses or not at all among most people. Examples of such diseases include some asthma caused by high- and low-molecular weight agents, extrinsic allergic alveolitis, chronic beryllium disease, allergic contact dermatitis, and possibly a few others such as hard metal pneumoconiosis. For such effects, which are becoming increasingly important in occupational and environmental health practice, efforts to define the basis for host variability are crucial in providing the links between exposure dose and response and are central to developing control strategies. Without attempting to dampen enthusiasm for the heuristically attractive research involving gene-environment interactions. it is worth recognizing that neither the identification of major polymorphisms of xenobiotic metabolizing genes nor knowledge on gene-environment interactions has yet proved to be of practical value in occupational health. Most likely. differences are not as great, or consequences of any differences in one system are offset by redundancies elsewhere. In contrast, the area of idiosyncratic reactions to chemicals has received less attention from toxicologists, but given their increasing importance at low environmental exposures, this is a research field with much practical value.
Is7/L21
9
POLYMORPHIC CYP GENES AND DISEASE PREDISPOSmON - WHAT HAVE THE STUDIES SHOWN SO FAR?
M. Watanabe. Iwata Prefectural University, Takizawa and Tohoku
University, Sendai, Japan Molecular genetic technology prompt us to evoke advances in the study of oxidizing enzymes in human and to allow the dissection of many of the molecular mechanism of cancer and the related diseases. Indeed, several tumors are now known to result in the establishment of heritable cancer families with high incidence of the related tumors. Most of organisms have developed complex mechanisms by which they protect themselves from environmental hazards and intoxicants. In the majority of cases, the ability to metabolize and hence either detoxify and activate the xenobiotic chemicals provides the first line of regulatory mechanism, especially against low molecular weight of chemicals. A number of drug metabolizing enzymes superfamilies including cytochrome p450 (CYP) dependent monooxygenase and the other enzymes and the receptor proteins are thought to evolve as adaptive response to environmental insult. We were able to prepare the polymorphic genes from human materials and to predict that any alteration in individuals would result in a variable susceptibility to some chemical-induced diseases, such as cancer and specific occupational diseases. Then the interaction between the genetic and phenotypic polymorphisms of the drug metabolizing enzymes and the related environmental facter, such as smoking habit, have to be considered more precisely to evaluate the genesis of the specific disease, and to provide the preposition of the diseases.
IS7/L31 POLYMORPHISMS IN XENOBIOTIC CONJUGATION AND DISEASE PREDISPOSITION
J. Brockmoller *, L. Cascorbi, R. Kerb, L. Roots. Institute of Clinical Pharmacology; Charite, Humboldt University Berlin, Germany Inherited polymorphisms in human glutahione S-transferases and arylamine N-acetyltransfe rases modify the individual risk for disease from environmental or occupational exposure. Numerous studies have shown that glutathione S-transferase Ml deficiency increases the risk for lung and urinary-bladder cancer although the overall risk increase was only about 1.3 fold. Similarly, in a summary of all studies, the slow acetylation trait (NAT2) increased the risk for bladder cancer by about 1.3 fold. These overall effects may be due to multiple interactions between genes and different environmental exposures in the different studies. Risk modification by polymorphic GSIs and NATs depends in a nonlinear fashion on the external exposure, e.g. slow NAT2 was only a risk factor in the subgroup of bladder cancer patients who were exposed to aromatic amines from cigarette smoking (Cancer Res. 56: 3915, 1996). But, the effect of enzyme polymorphisms may also depend in a nonlinear fashion on the enzyme activity, e.g. persons with intermediate activity may be better protected than those with very low or with a very high activity. Our data consistently show, that very fast acetylators (carriers of NAT2*4/4) are at higher risk to get lung and laryngeal cancer from tabacco smoke (Cancer Res. 56, 3961, 1996). It was proposed that consideration of NAT1 polymorphism together with the NAT2 polymorphism might allow a better understanding of N-acetylation in arylamine toxicity. However, the functional difference between the frequent NATl variants *3, *10, and *11 is still controversial and according to own data, some functional differences ascribed to NATI mutations may be due to genetic linkage with NAT2. We found a highly significant linkage between the NAT] *10 allele andNAT2 *4 (p < 0.0001). Such "gene-dose" effects may also be relevant in polymorphic GSTs and therefore recently developed methods to differentiate
S7. Genetic Susceptibility in Occupational Toxicology
IS7/L1 I
GENE-ENVIRONMENT INTERACTION IN OCCUPATIONAL TOXICOLOGY
H. Vainio. International Agency for Research on Cancer, Lyon,
France Occupational chemicals are metabolized through a variety of enzymes, the regulation of which is complex. Common variations (' polymorphisms') in gene sequence can result in altered protein, which may have functional consequences. Since polyrnorphisms evolve over time in populations, ethnic differences in the prevalence of variants are often observed. The results of this work on polymorphic metabolic genes have yet to explain consistent differences in risk that theory might predict. Observed differences in risk between high- and low-risk genotypes are typically threefold or less. If genetic host factors modify the carcinogenic and toxic effects of many: chemical hazards, their role appears to be particularly important in that subset of health effects that are more clearly ' idiosyncratic' : effects seen at low dose among a small fraction of individuals but only at far higher doses or not at all among most people. Examples of such diseases include some asthma caused by high- and low-molecular weight agents, extrinsic allergic alveolitis, chronic beryllium disease, allergic contact dermatitis, and possibly a few others such as hard metal pneumoconiosis. For such effects, which are becoming increasingly important in occupational and environmental health practice, efforts to define the basis for host variability are crucial in providing the links between exposure dose and response and are central to developing control strategies. Without attempting to dampen enthusiasm for the heuristically attractive research involving gene-environment interactions. it is worth recognizing that neither the identification of major polymorphisms of xenobiotic metabolizing genes nor knowledge on gene-environment interactions has yet proved to be of practical value in occupational health. Most likely. differences are not as great, or consequences of any differences in one system are offset by redundancies elsewhere. In contrast, the area of idiosyncratic reactions to chemicals has received less attention from toxicologists, but given their increasing importance at low environmental exposures, this is a research field with much practical value.
Is7/L21
9
POLYMORPHIC CYP GENES AND DISEASE PREDISPOSmON - WHAT HAVE THE STUDIES SHOWN SO FAR?
M. Watanabe. Iwata Prefectural University, Takizawa and Tohoku
University, Sendai, Japan Molecular genetic technology prompt us to evoke advances in the study of oxidizing enzymes in human and to allow the dissection of many of the molecular mechanism of cancer and the related diseases. Indeed, several tumors are now known to result in the establishment of heritable cancer families with high incidence of the related tumors. Most of organisms have developed complex mechanisms by which they protect themselves from environmental hazards and intoxicants. In the majority of cases, the ability to metabolize and hence either detoxify and activate the xenobiotic chemicals provides the first line of regulatory mechanism, especially against low molecular weight of chemicals. A number of drug metabolizing enzymes superfamilies including cytochrome p450 (CYP) dependent monooxygenase and the other enzymes and the receptor proteins are thought to evolve as adaptive response to environmental insult. We were able to prepare the polymorphic genes from human materials and to predict that any alteration in individuals would result in a variable susceptibility to some chemical-induced diseases, such as cancer and specific occupational diseases. Then the interaction between the genetic and phenotypic polymorphisms of the drug metabolizing enzymes and the related environmental facter, such as smoking habit, have to be considered more precisely to evaluate the genesis of the specific disease, and to provide the preposition of the diseases.
IS7/L31 POLYMORPHISMS IN XENOBIOTIC CONJUGATION AND DISEASE PREDISPOSITION
J. Brockmoller *, L. Cascorbi, R. Kerb, L. Roots. Institute of Clinical Pharmacology; Charite, Humboldt University Berlin, Germany Inherited polymorphisms in human glutahione S-transferases and arylamine N-acetyltransfe rases modify the individual risk for disease from environmental or occupational exposure. Numerous studies have shown that glutathione S-transferase Ml deficiency increases the risk for lung and urinary-bladder cancer although the overall risk increase was only about 1.3 fold. Similarly, in a summary of all studies, the slow acetylation trait (NAT2) increased the risk for bladder cancer by about 1.3 fold. These overall effects may be due to multiple interactions between genes and different environmental exposures in the different studies. Risk modification by polymorphic GSIs and NATs depends in a nonlinear fashion on the external exposure, e.g. slow NAT2 was only a risk factor in the subgroup of bladder cancer patients who were exposed to aromatic amines from cigarette smoking (Cancer Res. 56: 3915, 1996). But, the effect of enzyme polymorphisms may also depend in a nonlinear fashion on the enzyme activity, e.g. persons with intermediate activity may be better protected than those with very low or with a very high activity. Our data consistently show, that very fast acetylators (carriers of NAT2*4/4) are at higher risk to get lung and laryngeal cancer from tabacco smoke (Cancer Res. 56, 3961, 1996). It was proposed that consideration of NAT1 polymorphism together with the NAT2 polymorphism might allow a better understanding of N-acetylation in arylamine toxicity. However, the functional difference between the frequent NATl variants *3, *10, and *11 is still controversial and according to own data, some functional differences ascribed to NATI mutations may be due to genetic linkage with NAT2. We found a highly significant linkage between the NAT] *10 allele andNAT2 *4 (p < 0.0001). Such "gene-dose" effects may also be relevant in polymorphic GSTs and therefore recently developed methods to differentiate