Clotrimazole as an inhibitor of benzo[a]pyrene metabolite-DNA adduct formation in vitro and of microsomal mono-oxygenase activity
Kahl, R.; Friederici, D.E.; Kahl, G.F.; Ritter, W.; Krebs, R.
Drug Metabolism and Disposition the Biological Fate of Chemicals 8(4): 191-196
1980
ISSN/ISBN: 0090-9556 PMID: 6105049 Document Number: 162288
The fungistatic drug clotrimazole {1- values down to 7 .times. 10-8 M. The mechanism of inhibition was noncompetitive in phenobarbital-stimulated microsomes. Microsomal epoxide hydratase in vitro was enhanced up to 450% by clotrimazole and 1 of the analogs in concentrations between 5-500 .mu.M. Clotrimazole spectrally interacted with reduced cytochrome P-450, exhibiting a double-banded Soret region with peaks at 427 and 446 nm, and partially prevented cytochrome P-450-CO complex formation. When administered in vivo, clotrimazole effectively induced cytochrome P-450 content, mono-oxygenase activity and epoxide hydratase activity in rat liver microsomes. The induction pattern was similar to that obtained with phenobarbital. The analogues were less potent inducers. The enzymic and DNA-hydrocarbon-binding inhibitory effects of clotrimazole indicate that the drug may be useful in cancer therapy.