Variability of coumarin 7- and 3-hydroxylation in a Jordanian population is suggestive of a functional polymorphism in cytochrome P450 CYP2A6.
OBJECTIVE
To determine the variability of coumarin 7- and 3-hydroxylation in a human population and to evaluate the evidence for the existence of genetic polymorphism in these pathways. 7-Hydroxylation of coumarin is considered to be a detoxication pathway, whilst 3-hydroxylation, which predominates in rats, leads to hepatotoxicity in the rat. Coumarin metabolic phenotypes could aid in refining the risk evaluation for humans of dietary and environmental exposure to coumarin and for the chronic use of coumarin in high doses as a drug to treat lymphoedema and certain cancers.


METHODS
Healthy male and female Jordanian volunteers (n = 103) were administered 2 mg coumarin by mouth and collected their 0-8-h urines. These, together with pre-dose blank urines, were analysed by selected-ion monitoring gas chromatography mass spectrometry for their content of the coumarin metabolites 7-hydroxycoumarin (70HC) and 2-hydroxyphenylacetic acid (2OHPAA), the latter arising from the 3-hydroxylation pathway.


RESULTS
After coumarin administration, excretion of both 70HC and 2OHPAA was highly variable. A coumarin metabolic ratio (2OHPAA/7OHC) was suggestive of polymorphism. At least one subject had a metabolic response similar to an individual known to be both phenotypically and genotypically (CYP2A6 gene) 7-hydroxylation-deficient.


CONCLUSIONS
In the light of the finding of high variability and possible polymorphism in both the 7- and 3-hydroxylation of coumarin in a human population. we recommend a reappraisal of the risk evaluation of human exposure to coumarin, particularly in pharmaceutical doses.
Hadidi
H
H
Department of Pharmacology, Faculty of Medicine, Jordan University of Science and Technology, Irbid.
Irshaid
Y
Y
Vågbø
C B
CB
Brunsvik
A
A
Cholerton
S
S
Zahlsen
K
K
Idle
J R
JR
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D003374:Coumarins / Q000009:adverse effects / Q000378:metabolism*; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D014644:Genetic Variation; D006801:Humans; D006900:Hydroxylation; D007597:Jordan; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D010648:Phenylacetates / Q000652:urine; D011110:Polymorphism, Genetic; D014468:Umbelliferones / Q000652:urine
D003374:Coumarins; D010648:Phenylacetates; D014468:Umbelliferones; C031477:7-hydroxycoumarin; 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; C005756:2-hydroxyphenylacetic acid