Policosanol modulates HMG-CoA reductase activity in cultured fibroblasts.
BACKGROUND
Cholesterol biosynthesis is strictly controlled by 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase.


METHODS
Transfer of cultured fibroblasts to a lipid-depleted medium (LDM) up-regulates the enzyme levels. This, in turn, is followed by an accelerated biosynthesis of cholesterol.


RESULTS
Exposure of Vero fibroblasts to LDM and policosanol (0.5-50 microg/mL), a new cholesterol-lowering drug purified from sugarcane (Saccharum officinarum L.) wax, decreased in a dose-dependent manner cholesterol biosynthesis from [14C]-acetate and 3H-water, but not from [14C]-mevalonate.


CONCLUSIONS
This suggests an effect on HMG-CoA reductase, the rate-controlling enzyme in cholesterol biosynthesis. When enzyme activity was measured in the presence of various concentrations of policosanol (0.5-50 microg/mL), reductase was not suppressed. Therefore, there was no evidence for a competitive or noncompetitive inhibition of enzyme activity. However, after treatment of intact cells with policosanol (50 microg/mL) in the presence of LDM, a suppressive effect on enzyme activity was observed, suggesting a modulatory effect of policosanol on reductase activity. The previous inhibition of enzyme up-regulation by policosanol suggests to date a depression of de novo synthesis of HMG-CoA reductase and/or stimulation of its degradation. However, the exact mechanism by which policosanol inhibits the activity of HMG-CoA reductase still remains unclear. Further studies are needed to clarify the precise mechanism of its inhibitory action on cholesterol biosynthesis.
Laboratorio de Bioquímica, Centro de Productos Naturales, Centro Nacional de Investigación Científica, Havana, Cuba. dalmer@ip.etccsa.cu
R
R
Menéndez
A M
AM
Amor
I
I
Rodeiro
R M
RM
González
P C
PC
González
J L
JL
Alfonso
R
R
Más
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism; D005233:Fatty Alcohols / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D014709:Vero Cells
D000924:Anticholesteremic Agents; D005233:Fatty Alcohols; C080710:policosanol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases