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Effect of trans-1,4-bis(2-chlorobenzylaminomethyl) Cyclohexane Dihydrochloride and Carbon Monoxide on Hepatic Cholesterol Biosynthesis From 4,4,-dimethyl Sterols in Vitro

Effect of trans-1,4-bis(2-chlorobenzylaminomethyl) Cyclohexane Dihydrochloride and Carbon Monoxide on Hepatic Cholesterol Biosynthesis From 4,4,-dimethyl Sterols in Vitro

G F Gibbons, K A Mitropoulos

Biochim Biophys Acta. 1975 Feb 20;380(2):270-81.

PMID: 1120146

Abstract:

The drug trans-1,4-bis(2-chlorobenzylaminomethyl)cyclohexane dihydrochloride (AY-9944) almost completely inhibited the conversion of [2-14C] mevalonic acid, dihydro[14C]lanosterol, 4,4-dimethyl-5alpha-[2-3H2]cholesta-8,14-dien-3beta-ol and 4,4-dimethyl-5alpha-[2-3H2]cholest-8(14)-en-3beta-ol to 5alpha-cholest-7-en-3beta-ol and cholesterol by cell-free systems of rat liver. With the first three precursors, the inhibition was accompanied by an accumulation of radioactive 5alpha-cholesta-8,14-dien-3beta-ol, but this material could not be detected during inhibition of cholesterol biosynthesis from 4,4-dimethyl-5alpha-[2-3H2] cholest-8(14)-en-3beta-ol. Regardless of the nature of the precursor, trans-1,4-bis(2-chlorobenzylaminomethyl)cyclohexane dihydrochloride did not result in the accumulation of any delta5,7 sterols. Non-radioactive 5alpha-cholest-8(14)-en-3beta-ol inhibited the conversion of dihydro[14C]lanosterol to 4,4-dimethyl-5alpha-cholesta-8,14-dien-3beta-ol. Carbon monoxide resulted in a decrease in the rate of conversion of dihydro[14C]lanosterol to 4,4-dimethyl-5alpha-cholesta-8,14-dien-3beta-ol but had no effect on the rate of conversion of 4,4-dimethyl-5alpha-[2-3H2]cholesta-8,14-dien-3beta-ol to 5alpha-cholest-7-en-3beta-ol and cholesterol suggesting that cytochrome P-450 is involved neither in the oxidative removal of the 4-methyl groups nor in the oxidative introduction of the delta5 bond during cholesterol biosynthesis. In addition, the process of cholesterol and 5alpha-cholest-7-en-3beta-ol biosynthesis from 4,4-dimethyl-5alpha-[2-3H2]cholest-8(14)-en-3beta-ol was inhibited by carbon monoxide at a stage after the formation of 5alpha-cholest-8(14)-en-3beta-ol.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP80999	5α-Cholest-7-en-3β-ol		80-99-9	Price

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