Hepatic cytochrome P450 reductase-null mice reveal a second microsomal reductase for squalene monooxygenase.
Squalene monooxygenase is a microsomal enzyme that catalyzes the conversion of squalene to 2,3(s)-oxidosqualene, the immediate precursor to lanosterol in the cholesterol biosynthesis pathway. Unlike other flavoprotein monooxygenases that obtain electrons directly from NAD(P)H, squalene monooxygenase requires a redox partner, and for many years it has been assumed that NADPH-cytochrome P450 reductase is this requisite redox partner. However, our studies with hepatic cytochrome P450-reductase-null mice have revealed a second microsomal reductase for squalene monooxygenase. Inhibition studies with antibody to P450 reductase indicate that this second reductase supports up to 40% of the monooxygenase activity that is obtained with microsomes from normal mice. Studies carried out with hepatocytes from CPR-null mice demonstrate that this second reductase is active in whole cells and leads to the accumulation of 24-dihydrolanosterol; this lanosterol metabolite also accumulates in the livers of CPR-null mice, indicating that cholesterol synthesis is blocked at lanosterol demethylase, a cytochrome P450.
Li
Li
L
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Porter
Todd D
TD
D000818:Animals; D002474:Cell-Free System / Q000502:physiology; D002478:Cells, Cultured; D015786:Cytochromes b5 / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D050603:Squalene Monooxygenase / Q000502:physiology*
D015786:Cytochromes b5; D050603:Squalene Monooxygenase; D009251:NADPH-Ferrihemoprotein Reductase