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

• Published in: International journal of hygiene and environmental health 2003-06, Vol.206 (3), p.149-171
• Main Authors: Thier, Ricarda, Brüning, Thomas, Roos, Peter H., Rihs, Hans-Peter, Golka, Klaus, Ko, Yon, Bolt, Hermann M.
• Format: Article
• Language: English
• Subjects: Air. Soil. Water. Waste. Feeding; Arylamine N-Acetyltransferase - genetics; Arylamine N-Acetyltransferase - pharmacology; Biological and medical sciences; cancer; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - pharmacology; cytochrome P450; Environment. Living conditions; Environmental Health; Genetic Markers; Genetic Predisposition to Disease; glutathione S-transferases; Glutathione Transferase - genetics; Glutathione Transferase - pharmacology; Humans; Isoenzymes; Medical sciences; Molecular epidemiology; N-acetyl-transferases; Occupational Health; Polymorphism, Genetic; polymorphisms; Public health. Hygiene; Public health. Hygiene-occupational medicine; susceptibility; Toxicology - trends; Xenobiotics - adverse effects
• ISSN: 1438-4639; 1618-131X
• DOI: 10.1078/1438-4639-00209

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 (CYP1B1*3) 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