Abstract
CYP2A13 has been identified as an efficient catalyst for the metabolisms of coumarin, aflatoxin B1 (AFB1), and several tobacco-specific carcinogens. The reported CYP2A13 polymorphisms with missense variations have been studied for their functional consequences, and CYP2A13*4 (R101Q) variant was found to be a null enzyme in metabolizing 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), AFB1, and 5-methoxypsoralen. In the present study, CYP2A13*4 was expressed in Sf9 cells and evaluated for coumarin 7-hydroxylation activity. Our results demonstrated that CYP2A13*4 showed no activity in coumarin 7-hydroxylation. Furthermore, computer modeling studies were conducted to probe the mechanisms underlying the loss of catalytic activity of CYP2A13*4. The results suggested that the R101Q alteration may result in the absence of several hydrogen bonds involved in heme binding and thus lead to the loss of function in CYP2A13*4. In addition, for the first time, the distribution frequencies of all eight known CYP2A13 missense alleles were examined in a Chinese Han population. The distribution frequencies of CYP2A13*3 allele and CYP2A13*4 allele in the Chinese Han population were statistically significantly different from the reported values in Japanese. Considering that the two variants of CYP2A13 are incapable of metabolic activation of NNK and AFB1, the susceptibility to NNK or AFB1 exposure between the Chinese Han population and Japanese can be different.
Footnotes
This work was supported by the National Major Projects of China [Grants 2012ZX09506001-004, 2009ZX09304-003]; and the National Natural Science Foundation of China [Grant 30771825].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- AFB1
- aflatoxin B1
- NNK
- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
- ASA
- allele-specific amplification
- P450
- cytochrome P450
- PCR
- polymerase chain reaction
- MD
- molecular dynamics.
- Received November 30, 2011.
- Accepted February 7, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|