Abstract
During the last couple of years, cytochrome P450 2A6 (CYP2A6; coumarin 7-hydroxylase) has received a lot of attention because it has been shown that it is the principle human nicotineC-oxidase. This enzyme also activates a number of structurally unrelated precarcinogens including many nitrosamines and aflatoxin B1, and metabolizes certain clinically used drugs. There is a pronounced interindividual and interethnic variability in CYP2A6 levels and activity, and much of this can be attributed to polymorphisms in the CYP2A6 gene, where a few inactivating mutations as well as gene deletions have been described. The frequency of the inactive alleles is low in European populations and very few poor metabolizers for the probe drug coumarin have been described in these populations. In contrast, a relatively high allele frequency (15–20%) of the CYP2A6 gene deletion has been found in Asians, resulting in a generally reduced activity in these populations. Because of the importance of CYP2A6 in nicotine metabolism, it has been suggested that the CYP2A6 genotype influences the interindividual differences in smoking behavior as well as lung cancer susceptibility. Several case-control studies have been conducted in this area, but these have yielded conflicting results. The recent progress in the field of CYP2A6 genetics and the development of more specific genotyping methods will facilitate molecular epidemiological studies aimed at clarifying these important issues.
Footnotes
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Send reprint requests to: Mikael Oscarson, Ph.D., Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden. E-mail:mikael.oscarson{at}imm.ki.se
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The research in my laboratory was supported by grants from the Swedish Society for Medical Research, the Swedish Cancer Society, and the Swedish Medical Research Council.
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↵2 Z. Bao, T. Su, X. Ding, and J.-Y. Hong (2000) Metabolism of nicotine and cotinine by human cytochrome P450 2A13 (CYP2A13). 13th International Symposium on Microsomes and Drug Oxidations, Stresa, Italy, Poster 137.
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↵3 In this review, I have used the nomenclature system for CYP2A6 alleles recommended by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (seehttp://www.imm.ki.se/CYPalleles).
- Abbreviations used are::
- P450 or CYP
- cytochrome P450
- PM
- poor metabolizer
- PCR
- polymerase chain reaction
- Received September 12, 2000.
- Accepted October 30, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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