Detoxicating
enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1) and
NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction
of quinone-like compounds. The protective role of the polymorphic
NQO1 and NQO2 enzymes is especially of interest in the liver as the
major site of drug bioactivation to chemically reactive drug metabolites.
In the current study, we quantified the concentrations of NQO1 and
NQO2 in 20 human liver donors and NQO1 and NQO2 activities with quinone-like
drug metabolites. Hepatic NQO1 concentrations ranged from 8 to 213
nM. Using recombinant NQO1, we showed that low nM concentrations of
NQO1 are sufficient to reduce synthetic amodiaquine and carbamazepine
quinone-like metabolites in vitro. Hepatic NQO2 concentrations
ranged from 2 to 31 μM. NQO2 catalyzed the reduction of quinone-like
metabolites derived from acetaminophen, clozapine, 4′-hydroxydiclofenac,
mefenamic acid, amodiaquine, and carbamazepine. The reduction of the
clozapine nitrenium ion supports association studies showing that
NQO2 is a genetic risk factor for clozapine-induced agranulocytosis.
The 5-hydroxydiclofenac quinone imine, which was previously shown
to be reduced by NQO1, was not reduced by NQO2. Tacrine was identified
as a potent NQO2 inhibitor and was applied to further confirm the
catalytic activity of NQO2 in these assays. While the in vivo relevance of NQO2-catalyzed reduction of quinone-like metabolites
remains to be established by identification of the physiologically
relevant co-substrates, our results suggest an additional protective
role of the NQO2 protein by non-enzymatic scavenging of quinone-like
metabolites. Hepatic NQO1 activity in detoxication of quinone-like
metabolites becomes especially important when other detoxication pathways
are exhausted and NQO1 levels are induced.