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 exclusively by 7-hydroxylation. We have identified an individual who is homozygous for a single amino acid substitution (Leu160His) 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.
Hadidi
H
H
Institute for Cancer Research and Molecular Biology, Norwegian University of Scinece and Technology, Trondheim.
Zahlsen
K
K
Idle
J R
JR
Cholerton
S
S
D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D002648:Child; D003374:Coumarins / Q000378:metabolism*; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011110:Polymorphism, Genetic; D013329:Structure-Activity Relationship
D003374:Coumarins; D003577:Cytochrome P-450 Enzyme System; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6