Single copy of variant CYP2A6 alleles does not confer susceptibility to liver dysfunction in patients treated with coumarin.
OBJECTIVE
Coumarin, used in the treatment of chronic venous diseases, is mainly metabolized to non-toxic 7-hydroxy-coumarin by CYP2A6. At least, 3 variant alleles, CYP2A6*2, CYP2A6*3 and CYP2A6*4A, have been shown to encode catalytically defective proteins. Sporadic elevation of liver enzymes has been reported on the chronic administration ofcoumarin. We sought to determine if susceptibility to coumarin-associated liver dysfunction is genetically determined by polymorphism in CYP2A6 and impairment of the 7-hydroxylation ofcoumarin. Additionally, we were interested in the effect of polymorphism on smoking because of the predominant role of CYP2A6 in the metabolism of nicotine.


METHODS
The investigation was performed prospectively within a randomized double-blind clinical trial of the coumarin-containing drug SB-LOT (90 mg coumarin + 540 mg troxerutin/d) vs. placebo in 231 German patients with chronic venous insufficiency. Monitoring of the hepatic status involved regular measurements of liver function during the 16-week treatment. Genotyping of CYP2A6 was carried out by means of PCR and confirmed by DNA sequencing analysis.


RESULTS
The allelic frequencies of the variant CYP2A6*2 and CYP2A6*3 alleles were 0.023 and 0.014, respectively. There was no significant difference in the incidence of liver dysfunction between heterozygotes with CYP2A6*2, CYP2A6*3 and wild-type homozygotes. CYP2A6 polymorphism had no significant effect on smoking behavior.


CONCLUSIONS
No evidence was obtained that the studied polymorphism in CYP2A6 is a determinant of the coumarin-associated liver dysfunction.
Burian
M
M
Department of Pharmacology and Toxicology, Philipps University, Marburg, Germany. burian@em.uni-frankfurt.de
Freudenstein
J
J
Tegtmeier
M
M
Naser-Hijazi
B
B
Henneicke-von Zepelin
H H
HH
Legrum
W
W
D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D003374:Coumarins / Q000009:adverse effects* / Q000627:therapeutic use; D065637:Cytochrome P-450 CYP2A6; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006896:Hydroxyethylrutoside / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008107:Liver Diseases / Q000235:genetics* / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012907:Smoking / Q000235:genetics / Q000378:metabolism; D014689:Venous Insufficiency / Q000188:drug therapy / Q000378:metabolism
D000925:Anticoagulants; D003374:Coumarins; D004338:Drug Combinations; D006896:Hydroxyethylrutoside; C005865:troxerutin; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6