Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1 - PubMed (original) (raw)

Review

Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1

Tsutomu Shimada et al. Cancer Sci. 2004 Jan.

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitously distributed environmental chemicals. PAHs acquire carcinogenicity only after they have been activated by xenobiotic-metabolizing enzymes to highly reactive metabolites capable of attacking cellular DNA. Cytochrome P450 (CYP) enzymes are central to the metabolic activation of these PAHs to epoxide intermediates, which are converted with the aid of epoxide hydrolase to the ultimate carcinogens, diol-epoxides. Historically, CYP1A1 was believed to be the only enzyme that catalyzes activation of these procarcinogenic PAHs. However, recent studies have established that CYP1B1, a newly identified member of the CYP1 family, plays a very important role in the metabolic activation of PAHs. In CYP1B1 gene-knockout mice treated with 7,12-dimethylbenz[a]anthracene and dibenzo[a,l]pyrene, decreased rates of tumor formation were observed, when compared to wild-type mice. Significantly, gene expression of CYP1A1 and 1B1 is induced by PAHs and polyhalogenated hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin through the arylhydrocarbon receptor. Differences in the susceptibility of individuals to the adverse action of PAHs may, in part, be due to differences in the levels of expression of CYP1A1 and 1B1 and to genetic variations in the CYP1A1 and 1B1 genes.

PubMed Disclaimer

Similar articles

Cited by

References

    1. Conney AH. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G.H.A. Clowes memorial lecture. Cancer Res 1982; 4: 4875–917. - PubMed
    1. Guengerich FP, Shimada T. Oxidation of toxic and carcinogenic chemicals by human cytochrome P‐450 enzymes. Chem Res Toxicol 1991; 4: 391–407. - PubMed
    1. Shimada T, Hayes CL, Yamazaki H, Amin S, Hecht SS, Guengerich FP, Sutter TR. Activation of chemically diverse procarcinogens by human cytochrome P450 1B1. Cancer Res 1996; 56: 2979–84. - PubMed
    1. Shimada T, Iwasaki M, Martin MV, Guengerich FP. Human liver microsomal cytochrome P‐450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA1535/pSK1002. Cancer Res 1989; 49: 3218–28. - PubMed
    1. Yamazaki H, Inui Y, Yun CH, Guengerich FP, Shimada T. Cytochrome P450 2E1 and 2A6 enzymes as major catalysts for metabolic activation of N‐ni‐trosodialkylamines and tobacco‐related nitrosamines in human liver microsomes. Carcinogenesis 1992; 13: 1789–94. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources