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.
Menéndez
R
R
Laboratorio de Bioquímica, Centro de Productos Naturales, Centro Nacional de Investigación Científica, Havana, Cuba. dalmer@ip.etccsa.cu
Amor
A M
AM
Rodeiro
I
I
González
R M
RM
González
P C
PC
Alfonso
J L
JL
Más
R
R
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