Generation of a free radical from calphostin C by microsomal cytochrome P450 reductase in rat and human liver.
Calphostin C (cal C) is a potent and specific protein kinase C inhibitor that is thought to be photoactivated to generate a reactive perylenesemiquinone free radical intermediate. In this electron spin resonance spectrometry study, we show, for the first time, an enzymatic light-independent mechanism of cal C free radical formation. Such a free radical was generated in liver microsomes from rat and humans, and its formation was dependent on the presence of NADPH, functional microsomes, and protein and cal C concentrations. Inhibitor and purified enzyme studies showed that cytochrome P450 reductase is responsible for the cal C free radical observed, which is probably a perylenesemiquinone.
Patterson
L H
LH
Department of Pharmaceutical Sciences, De Montfort University, Leicester, U.K.
Jones
S
S
Gescher
A
A
D000818:Animals; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005609:Free Radicals; D006801:Humans; D008099:Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000502:physiology*; D009281:Naphthalenes / Q000378:metabolism*; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats
D004791:Enzyme Inhibitors; D005609:Free Radicals; D009281:Naphthalenes; D009249:NADP; D009251:NADPH-Ferrihemoprotein Reductase; D011493:Protein Kinase C; C058819:calphostin C