The effect of enzyme inhibition on the metabolism and activation of tacrine by human liver microsomes
作者： V Spaldin , S Madden , WF Pool , TF Woolf , BK Park
DOI: 10.1111/J.1365-2125.1994.TB04316.X
关键词: Pharmacology 、 Metabolite 、 Cytochrome P450 、 Enzyme 、 Microsome 、 Hydroxylation 、 Cytochrome P-450 Enzyme Inhibitors 、 Enzyme inhibitor 、 CYP1A2 、 Chemistry 、 Biochemistry
摘要: 1. Tacrine (1,2,3,4-tetrahydro-9-aminoacridine-hydrochloride: THA) underwent metabolism in vitro by a panel (n = 12) of human liver microsomes genotyped for CYP2D6, the presence NADPH, to both protein-reactive and stable metabolites. 2. There was considerable variation extent THA amongst livers. Protein-reactive metabolite formation showed 10-fold (0.6 +/- 0.1%-5.2 0.8% incubated radioactivity mg-1 protein) whilst metabolites 3-fold (24.3 1.7%-78.6 2.6% radioactivity). 3. Using cytochrome P450 isoform specific inhibitors CYP1A2 identified as major enzyme involved all routes metabolism. 4. high correlation between aromatic alicyclic hydroxylation (r 0.92, P < 0.0001) consistent with these biotransformations being catalysed same enzymes. 5. Enoxacin (ENOX), cimetidine (CIM) chloroquine (CQ) inhibited preferential decrease bioactivation protein-reactive, hence potentially toxic, species. The inhibitory potency ENOX CIM increased significantly upon pre-incubation NADPH. 6. Covalent binding correlated 7-OH-THA before 0.792, after 0.73, inhibition CIM, two-step mechanism metabolite(s) via 7-OH intermediate. 7. use may provide useful tool examining relationship toxicity vivo.
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