Inhibition of human and rabbit liver steroid and xenobiotic UDP-glucuronosyltransferases by tertiary amine drugs--implications for adverse drug reactions.
1. To investigate the hypothesis that disruption of glucuronidation of endogenous compounds by drugs represents a potential mechanism for pathogenesis of adverse drug reactions, the effects of a range of tertiary amine and amide drugs (many with effects on sex hormone function) on steroid hormone and xenobiotic UDP-glucuronosyltransferase activities in human and rabbit liver microsomes were studied in vitro. 2. Chlorpromazine, amitriptyline, imipramine, promethazine and cyproheptadine were consistently the most potent inhibitors of the glucuronidation of testosterone, androsterone, oestriol and 1-naphthol, the steroid activities being more susceptible to inhibition (up to 90%). 3. Carbamazepine, diphenhydramine, sulphadimethoxine, dimenhydrinate and (+/-)-chlorpheniramine had little effect on the UDPGT activities measured. 4. The structural features within this group of compounds required for inhibitory potency were the presence of a rigid tricyclic ring (e.g. phenothiazine) and either a dimethylaminopropyl or a methylpiperidine side-chain. 5. The implications of these data for involvement of disruption of the normal cellular function of glucuronidation in the pathogenesis of frequently observed adverse side-effects associated with these compounds are discussed.
Sharp
S
S
Department of Biochemical Medicine, University of Dundee, Ninewells Hospical and Medical School, Scotland, UK.
Mak
L Y
LY
Smith
D J
DJ
Coughtrie
M W
MW
D000588:Amines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D002746:Chlorpromazine / Q000494:pharmacology; D003533:Cyproheptadine / Q000494:pharmacology; D005260:Female; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D015394:Molecular Structure; D011398:Promethazine / Q000494:pharmacology; D011817:Rabbits; D013739:Testosterone / Q000378:metabolism
D000588:Amines; D012739:Gonadal Steroid Hormones; D000639:Amitriptyline; D003533:Cyproheptadine; D013739:Testosterone; D014453:Glucuronosyltransferase; D011398:Promethazine; D007099:Imipramine; D002746:Chlorpromazine