Carbonyl Reduction of Bupropion in Human Liver Cytosol
Molnari, Jillissa C.
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Human carbonyl reductases (CBRs) are a class of phase I drug metabolizing enzymes that metabolize numerous medications. Patients with pharmacogenetic variations in CBRs have suffered adverse clinical consequences when administered drugs that are CBR substrates. Thus there is a pressing need for pre-screening patients for pharmacogenetic variations in CBRs. Phenotyping patients for pharmacogenetic variations in drug metabolizing enzymes classically involves using a probe substrate for the enzyme. To date, a phenotypic probe for any of the CBRs is currently unknown. A novel probe substrate for CBRs may be bupropion, which is reduced to two diastereomers: erythrohydrobupropion (EBUP) and threohydrobupropion (TBUP). Although speculative, bupropion reduction is likely catalyzed by one or more CBRs. Hence, the objective of this study is to identify the carbonyl reductase(s) responsible for bupropion metabolism in human liver cytosol (HLC). The mean rate of formation (±s.d.) of EBUP and TBUP from bupropion in fresh HLC was 2.27(0.82) pmole/mg/min and 17.4(0.35) pmole/mg/min, respectively. This reaction was NADPH dependent and nullified in the presence of heat-inactivated HLC. The formation of EBUP and TBUP were analyzed in the presence of CBR inhibitors: menadione, flufenamic acid, and 4-methylpyrazole. Menadione, a specific inhibitor of the human carbonyl reductase (CR) enzyme, exhibited an IC50 towards bupropion reduction at 27.3 μM (EBUP) and 87.9 μM (TBUP). EBUP and TBUP formation was not inhibited by flufenamic acid or 4-methylpyrazole. To summarize, bupropion is metabolized to TBUP and EBUP in HLC by CR, suggesting that bupropion has promise as a novel probe substrate for identifying pharmacogenetic variations in CR.
Mentor: Alan L. Myers