Elsevier

Food and Chemical Toxicology

Volume 35, Issue 9, September 1997, Pages 903-907
Food and Chemical Toxicology

Research section
A single amino acid substitution (Leu160His) in cytochrome P450 CYP2A6 causes switching from 7-hydroxylation to 3-hydroxylation of coumarin

https://doi.org/10.1016/S0278-6915(97)00066-5Get rights and content

Abstract

Human populations are thought to metabolize coumarin almost exclusively by 7-hydroxylation. We have identified an individual who is homozygous for a single amino acid substitution (Leul60His) in the cytochrome P450 CYP2A6 arising from the variant CYP2A6∗2 allele. On administration of coumarin (2 mg orally) no detectable 7-hydroxycoumarin was excreted in the 0–8-hr urine, rather, approximately 50% of the dose was eliminated as 2-hydroxyphenylacetic acid, the end-product of coumarin 3-hydroxylation. His immediate family members, who were heterozygous for the CYP2A6∗2 allele, excreted little 2-hydroxyphenylacetic acid and mainly 7-hydroxycoumarin, when similarly tested. These findings raise a question regarding human risk evaluations for environmental coumarin exposures, since 7-hydroxylation is regarded as a detoxication pathway, but 3-hydroxylation as the process required to lead to macromolecular covalent binding of coumarin. Persons homozygous for the CYP2A6∗2 allele may constitute 1–25% of various populations.

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    Altered activity of CYP2A6 would clearly affect the bioavailability of nicotine in the systemic circulation and therefore would be a key factor involved with the addictive properties of nicotine itself. Several genetic single nucleotide polymorphisms (SNPs) have been identified that reduce function of CYP2A6*2, *4, and *5, which would lead to a prolonged effect of nicotine in the body, as well as increased gene replication of CYP2A6 in some individuals which would lead to lower sensitivity to the effects of nicotine (Ariyoshi, Sawamura, & Kamataki, 2001; Benowitz, Tyndale, Jacob, & Swan, 2002; Hadidi, Zahlsen, Idle, & Cholerton, 1997; Tyndale & Sellers, 2001). SNPs in the choline acetyltransferase (ChAT) gene (rs1880676, rs3810950, and rs868750) were also significantly associated with level of nicotine dependence (allele p-values were 0.01, 0.02, and 0.04, respectively).

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On sabbatical leave from the Jordan University of Science and Technology, Irbid, Jordan.

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