Compared effect of immunosuppressive drugs cyclosporine A and rapamycin on cholesterol homeostasis key enzymes CYP27A1 and HMG-CoA reductase.
Basic Clin Pharmacol Toxicol
; 100(6): 392-7, 2007 Jun.
Article
em En
| MEDLINE
| ID: mdl-17516993
ABSTRACT
Hyperlipidaemia, i.e. increase in total cholesterol and triglycerides, is a common side-effect of the immunosuppressive drugs rapamycin (RAPA) and cyclosporine A (CsA), and is probably related to inhibition of the 27-hydroxylation of cholesterol (acid pathway of bile acid biosynthesis). This might be one of the causes for the increase in plasma cholesterol, as 27-hydroxycholesterol is a potent suppressor of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), a key enzyme of cholesterol synthesis. As the sterol 27-hydroxylase (CYP27A1) inhibition by CsA is well known, we evaluated the effect of another immunosuppressive drug, RAPA, on this enzyme in HepG2 mitochondria, which confirmed the dose-dependent inhibition of mitochondrial CYP27A1 by cyclosporine (10-20 microM), while the inhibition by RAPA required a higher dose (50-100 microM). Corresponding K(i) was 10 microM for CsA (non-competitive inhibition) and 110 microM for RAPA (competitive inhibition). Cotreatment with both immunosuppressive drugs showed an additive inhibitory effect on CYP27A1 activity. Later, we analysed the effect of these immunosuppressants on HMGR expression in HepG2 cells, and a dose-dependent up-regulation of HMGR gene expression was observed. The results suggest that RAPA and CsA are both inhibitors of CYP27A1 activity with slightly different mechanisms and that they may accordingly increase HMGR expression.
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Base de dados:
MEDLINE
Assunto principal:
Colesterol
/
Ciclosporina
/
Sirolimo
/
Colestanotriol 26-Mono-Oxigenase
/
Hidroximetilglutaril-CoA Redutases
/
Imunossupressores
Limite:
Humans
Idioma:
En
Revista:
Basic Clin Pharmacol Toxicol
Assunto da revista:
FARMACOLOGIA
/
TOXICOLOGIA
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
França