Carbonyl Reduction of Bupropion in Human Liver Cytosol
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Authors
Molnari, Jillissa C.
Issue Date
2011-04-19T15:17:24Z
Type
Presentation
Language
en_US
Keywords
Carbonyl reductase , Cytosol , Liver
Alternative Title
Abstract
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.
Description
Mentor: Alan L. Myers