A SINGLE AMINO-ACID SUBSTITUTION (LEU160HIS) IN CYTOCHROME-P450 CYP2A6 CAUSES SWITCHING FROM 7-HYDROXYLATION TO 3-HYDROXYLATION OF COUMARIN

Human populations are thought to metabolize coumarin almost exclusivel y by 7-hydroxylation. We have identified an individual who is homozygo us for a single amino acid substitution (Leu160His) in the cytochrome P450 CYP2A6 arising from the variant CYP2A62 allele. On administratio n of coumarin (2 mg orally) no detectable 7-hydroxycoumarin was excret ed in the 0-8-hr urine, rather, approximately 50% of the dose was elim inated as 2-hydroxyphenylacetic acid, the end-product of coumarin 3-hy droxylation. His immediate family members, who were heterozygous for t he CYP2A62 allele, excreted little 2-hydroxyphenylacetic acid and mai nly 7-hydroxycoumarin, when similarly tested. These findings raise a q uestion regarding human risk evaluations for environmental coumarin ex posures, 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 CYP2A62 alle le may constitute 1-25% of various populations. (C) 1997 Elsevier Scie nce Ltd.