Journal Article

Single nucleotide polymorphisms, metabolic activation and environmental carcinogenesis: why molecular epidemiologists should think about enzyme expression

J.A. Williams

in Carcinogenesis

Volume 22, issue 2, pages 209-214
Published in print February 2001 | ISSN: 0143-3334
Published online February 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.2.209
Single nucleotide polymorphisms, metabolic activation and environmental carcinogenesis: why molecular epidemiologists should think about enzyme expression

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This commentary was written to stimulate thoughts on, and consideration of, enzyme expression data in target organs when investigating possible associations between polymorphisms in carcinogen activation enzymes, lifestyle/dietary factors and cancer risk. The lung and breast are taken as examples. There is overwhelming evidence for a genotoxic mechanism in lung cancer development, and compelling evidence for the contribution of genotoxins to breast cancer aetiology. A consistent association has been shown where lung cancer risk is decreased by a G→A polymorphism in the myeloperoxidase (MPO) gene, which is expressed in neutrophils recruited to the lung after chemical or immunological insults. In the breast, a consistent lack of association has been observed for women who are fast N-acetyltransferase type 2 (NAT2) acetylators consuming cooked meat. This could be explained by the lack of detectable NAT2-associated sulfamethazine acetylation activity in cytosols prepared from mammary tissue, suggesting a minor contribution to carcinogen activation. The recent identification in mammary cytosols of detectable sulfotransferase isoforms (SULT1A1 and SULT1A3), which have high catalytic efficiency for activating N-hydroxylated heterocyclic amines (HCAs, mutagens in cooked meat), offers a more important role for these enzymes in the metabolic activation of genotoxins in the breast. The possible contribution of MPO and lactoperoxidase enzymes to carcinogen activation in mammary tissue is also considered. Sulfotransferases and peroxidases have wide substrate specificity in terms of carcinogen activation (HCAs, aromatic amines and polycyclic aromatic hydrocarbons—all present in cooked meat and tobacco smoke) compared with NATs (HCAs and aromatic amines only). For gene–environment interactions, investigations into functional polymorphisms in SULT and peroxidase genes may, therefore, offer new evidence for the involvement of genotoxins in the initiation of carcinogenesis. Identification of the isoforms (if any) of carcinogen activation enzymes that are expressed in the organs of interest will help to determine which genes to investigate in these studies.

Keywords: CYP, cytochrome P450; HCAs, heterocyclic amines; MPO, myeloperoxidase; NAT, N-acetyltransferase; PAHs, polycyclic aromatic hydrocarbons; SULT, sulfotransferase.

Journal Article.  4969 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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