title: Xenobiotic and endobiotic inhibitors of cytochrome P-450dbl function, the target of the debrisoquine/sparteine type polymorphism.
abstract: Five to 10% of Caucasians are poor metabolizers (PM) of debrisoquine, sparteine, bufuralol and numerous other drugs. A deficiency in cytochrome P-450dbl (P-450dbl) function is the cause of this polymorphism of drug oxidation with autosomal recessive inheritance. In the present study, inhibition of bufuralol-1'-hydroxylase in human liver microsomes by drugs and chemicals was performed in a search for potential new substrates for this polymorphic enzyme. Among the 80 alkaloids and drugs tested, 25 were competitive inhibitors. In vitro competitive inhibition of bufuralol oxidation by a substance indicates that this compound is able to bind to the same enzymatic site as bufuralol. This may mean that the competing drug also is metabolized by P-450dbl and that its metabolism is subject to the same genetic variation as the oxidation of bufuralol. However, some of these competitive inhibitors are not oxidized by P-450dbl. In this case, however, they may interfere with the in vivo phenotyping procedure by inhibiting the formation of metabolites of test drugs such as debrisoquine, sparteine, metoprolol or dextrometorphan.
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003647:Debrisoquin / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D011110:Polymorphism, Genetic; D013034:Sparteine / Q000378:metabolism*; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007546:Isoquinolines; D015262:Xenobiotics; D013034:Sparteine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C043872:bufuralol 1'-hydroxylase; D003647:Debrisoquin