PT  - JOURNAL ARTICLE
AU  - W H Salam
AU  - D P Bloxham
TI  - Hypolipidemic effect of polymethylenemethane thiosulfonates: inhibitors of acetoacetyl coenzyme A thiolase.
DP  - 1987 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1099--1105
VI  - 241
IP  - 3
4099  - http://jpet.aspetjournals.org/content/241/3/1099.short
4100  - http://jpet.aspetjournals.org/content/241/3/1099.full
SO  - J Pharmacol Exp Ther1987 Jun 01; 241
AB  - A new series of bifunctional thiosulfonates of the general formula CH3SO2S-(CH2)n-SSO2CH3(SS1 polymethylene bis methane thiosulfonate) with variable polymethylene chain lengths (n = 6, 8, 10 and 12) were evaluated for their hypolipidemic action on serum cholesterol and triglyceride levels in rats. Their action was based on their specific inhibitory effect on cytoplasmic acetoacetyl-CoA thiolase, one of the key enzymes in cholesterol biosynthesis. These compounds inhibited the enzyme in vitro and in vivo. The inhibition in vitro was in the order of n = 12 greater than n = 10 greater than n = 8 greater than n = 6 greater than, where n is the number of methylene groups inserted between the two thiosulfonate groups. In vivo, the compounds produced variable hypocholesterolemic and/or hypotriglyceridemic effects when injected into groups of newly weaned rats fed standard chow, high fat or high carbohydrate diets. When the enzyme activity was measured in isolated liver homogenates in vitro after injections of the drugs in vivo, 80% of original thiolase activity was lost. This inhibition of enzyme activity did not seem to be rate limiting for their hypolipidemic action in vivo as these effects did not correlate with the inhibition of the isolated enzyme. The lack of correlation between in vitro and in vivo activity might be due to the compounds affecting other enzyme systems and/or due to their differential disposition in vivo.