Richard C. Zangar
Pacific Northwest National Laboratory, Richland, WA, 99352, USA
ABSTRACT
In this study, hepatic cholesterol levels were examined after treatment of rats with a series of structurally distinct drugs that induce the P450, CYP3A23. It was found that these agents decreased levels of unesterified and esterified cholesterol in microsomes, but generally increased levels of these lipids in crude membrane fractions from the rest of the liver. Troleandomycin induces CYP3A23 but is also an efficacious mechanisms-based inhibitor of this enzyme, so that treatment with this agent decreases overall CYP3A activity. Similar to other CYP3A23 inducers, treatment with troleandomycin suppressed cholesterol levels, suggesting that the effects on cholesterol are unlikely to be dependent upon increased CYP3A23 activity. Rather, it seem more likely that cholesterol processing within the liver is modified as a result of activation of a receptor, such as the pregnane X receptor, which regulates several enzymes involved in cholesterol metabolism as well as CYP3A23 expression.
PDF References
How to cite this article
Richard C. Zangar, 2005. Alterations in Hepatic Cholesterol Levels in Response to Drugs That Induce
Cytochrome P450 3A23. International Journal of Pharmacology, 1: 172-179.
DOI: 10.3923/ijp.2005.172.179
URL: https://scialert.net/abstract/?doi=ijp.2005.172.179
DOI: 10.3923/ijp.2005.172.179
URL: https://scialert.net/abstract/?doi=ijp.2005.172.179
REFERENCES
- Soccio, R.E. and J.L. Breslow, 2004. Intracellular cholesterol transport. Arteriosclerosis Thrombosis Vascular Biol., 24: 1150-1160.
Direct Link - Garver, W.S., R.P. Erickson, J.M. Wilson, T.L. Colton, G.S. Hossain, M.A. Kozloski and R.A. Heidenreich, 1997. Altered expression of caveolin-1 and increased cholesterol in detergent insoluble membrane fractions from liver in mice with Niemann-Pick disease type C. Biochem. Biophys. Acta, 1361: 272-280.
- Nelson, D.R., L. Koymans, T. Kamataki, J.J. Stegeman and R. Feyereisen et al., 1996. P450 superfamily: Update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics, 3: 1-42.
Direct Link - Kliewer, S.A., J.M. Lehmann, M.V. Milburn and T.M. Willson, 1999. The PPARs and PXRs: Nuclear xenobiotic receptors that define novel hormone signaling pathways. Recent Prog. Hormone Res., 54: 345-367.
Direct Link - Drocourt, L., J.M. Pascussi, E. Assenat, J.M. Fabre, P. Maurel and M.J. Vilarem, 2001. Calcium channel modulators of the dihydropyridine family are human pregnane x receptor activators and inducers of cyp3a, cyp2b and cyp2c in human hepatocytes. Drug Metab. Disposit., 29: 1325-1331.
Direct Link - Bastiaanse, E.M., K.M. Hold and A. van der Laarse, 1997. The effect of membrane cholesterol content on ion transport processes in plasma membranes. Cardiovascular Res., 33: 272-283.
Direct Link - Zangar, R.C., D.R. Davydov and S. Verma, 2004. Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicol. Applied Pharmacol., 199: 316-331.
CrossRefDirect Link