Studies on the mechanism of lanosterol 14 alpha-demethylation. A requirement for two distinct types of mixed-function-oxidase systems.
Carbon monoxide inhibited the removal of C-32 of dihydrolanosterol (I), but not of its metabolites 5 alpha-lanost-8-ene-3 beta,32-diol (II) and 3 beta-hydroxy-5 alpha-lanost-8-en-32-al (III). It appears therefore that cytochrome P-450 is a component of the enzyme system required to initiate oxidation of the 14 alpha-methyl group, but not of that responsible for the subsequent oxidation steps required for elimination of C-32 as formic acid. Non-radioactive compounds (II) and (III), when added to cell-free systems actively converting dihydrolanosterol into cholesterol, inhibited 14 alpha-demethylation measured by the rate of formation of labelled cholesterol from dihydro[1,7,15,22,26,30-14C]lanosterol or of labelled formic acid from dihydro[32-14C]lanosterol. However, neither compound (II) nor compound (III) accumulated radioactive label under these conditions. These observations could be attributed partly to inhibition of the initial oxidation of the 14 alpha-methyl group by compounds (II) and (III).
D000818:Animals; D002248:Carbon Monoxide; D055598:Chemical Phenomena; D002621:Chemistry; D002784:Cholesterol / Q000096:biosynthesis; D005561:Formates / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D007810:Lanosterol / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D013261:Sterols / Q000378:metabolism
D005561:Formates; D013261:Sterols; D007810:Lanosterol; D002248:Carbon Monoxide; D002784:Cholesterol; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases