Open Access
Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and1B1
Tsutomu Shimada
Osaka Prefectural Institute of Public Health, 1‐3‐69 Nakamichi, Higashinari‐ku, Osaka 537‐0025
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232‐0146, USA
Search for more papers by this authorYoshiaki Fujii‐Kuriyama
Corresponding Author
Center for Tsukuba Advanced Research Alliance, The University of Tsukuba, 1‐1‐1 Tennoudai, Tsukuba 305‐8577
Core Research for Evolutional Science and Technology (CREST) Japan, Science and Technology Corporation, 4‐1‐8 Honcho, Kawaguchi 322‐0012
To whom correspondence should be addressed. E‐mail: ykfujii@tara.tsukuba.ac.jpSearch for more papers by this authorTsutomu Shimada
Osaka Prefectural Institute of Public Health, 1‐3‐69 Nakamichi, Higashinari‐ku, Osaka 537‐0025
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232‐0146, USA
Search for more papers by this authorYoshiaki Fujii‐Kuriyama
Corresponding Author
Center for Tsukuba Advanced Research Alliance, The University of Tsukuba, 1‐1‐1 Tennoudai, Tsukuba 305‐8577
Core Research for Evolutional Science and Technology (CREST) Japan, Science and Technology Corporation, 4‐1‐8 Honcho, Kawaguchi 322‐0012
To whom correspondence should be addressed. E‐mail: ykfujii@tara.tsukuba.ac.jpSearch for more papers by this authorAbstract
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‐dimethyl‐benz[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.
Abbreviations:
-
- P450
-
- general term for cytochrome P450
-
- CYP
-
- individual forms of P450
-
- AhR
-
- arylhydrocarbon receptor
-
- PAH
-
- polycyclic aromatic hydrocarbon
-
- B[a]P
-
- benzo[a]pyrene
-
- 7,12‐DMBA
-
- 7,12‐dimethylbenz[a]anthracene
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- DB[a, l]P
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- dibenzo[a, l]pyrene
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- MC
-
- 3‐methylcholanthrene
-
- TCDD
-
- 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin. The suffix “dihydrodiol” or “diol” is used for the prefix “dihydroxydihydro” for individual polycyclic hydrocarbons
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