The rôle of cytochrome P-450 in cholesterol biosynthesis.

Abstract

The rates of cholesterol biosynthesis were studied in rat liver microsomal preparations incubated with [14C]lanosterol in the presence of gas mixtures of either carbon monoxide + oxygen (90:10, v/v) or nitrogen + oxygen (90:10, v/v). The presence of CO in the gas mixture resulted in a considerable decrease in the amount of cholesterol synthesized, and there was also a reduction in the radioactivity of the 4α‐methyl sterol fraction. The maximum rate of cholesterol biosynthesis in the presence of either N2+ O2 or CO + O2 occurred when the concentration of the substrate [14C]lanosterol was greater than 25 μM. The rate of cholesterol biosynthesis was constant for at least 40 min irrespective of the nature of the gas phase. During each time period studied, however, the amount of cholesterol formed was greater in the presence of N2+ O2. Removal of either ATP or NADPH from the incubation medium resulted in a significant decrease in the rate of microsomal cholesterol biosynthesis. Pre‐treatment of rats with phenobarbital resulted in a 35–40% increase in the rate of microsomal cholesterol biosynthesis from lanosterol. Incubations carried out under CO + O2 in which the flasks were illuminated with high intensity light of around 450 nm wavelength completely reversed the inhibitory effect of CO on cholesterol biosynthesis from lanosterol.