Markers of genetic susceptibility in human environmental hygiene and toxicology : the role of selected CYP, NAT and GST genes

Thier, Ricarda, Brüning, Thomas, Roos, Peter H., Rihs, Hans-Peter, Golka, Klaus, Ko, Yon, & Bolt, Hermann M. (2003) Markers of genetic susceptibility in human environmental hygiene and toxicology : the role of selected CYP, NAT and GST genes. International Journal of Hygiene and Environmental Health, 206(3), pp. 149-171.

View at publisher


Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the 2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B13) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1 *0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology.

Impact and interest:

122 citations in Scopus
Search Google Scholar™
94 citations in Web of Science®

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

ID Code: 77482
Item Type: Journal Article
Refereed: Yes
Keywords: Cancer, Cytochrome P-450, Glutathione S-transferases, Molecular epidemiology, N-acetyl-transferases, Polymorphisms, Susceptibility, 1 naphthylamine, 4 biphenylamine, aromatic amine, benzidine, carcinogen, cytochrome P450 1A1, cytochrome P450 1B1, cytochrome P450 2E1, ethylene oxide, glutathione transferase, methane, transcription factor, allele, bladder cancer, cellular immunity, Chinese, chronic disease, DNA polymorphism, environmental sanitation, enzyme activity, gene expression, gene targeting, genetic linkage, genetic marker, genetic susceptibility, genetic trait, genotype, head and neck cancer, human, molecular biology, null allele, occupational exposure, phenotype, protein expression, review, smoking, somatic mutation, squamous cell carcinoma, xenobiotic metabolism, Arylamine N-Acetyltransferase, Cytochrome P-450 Enzyme System, Environmental Health, Genetic Markers, Genetic Predisposition to Disease, Humans, Isoenzymes, Occupational Health, Polymorphism, Genetic, Toxicology, Xenobiotics
DOI: 10.1078/1438-4639-00209
ISSN: 1438-4639
Divisions: Current > Schools > School of Clinical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Copyright Owner: Copyright 2003 Urban und Fischer Verlag
Deposited On: 15 Oct 2014 23:10
Last Modified: 17 Oct 2014 03:28

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page