Regulation of CYP2B6 and CYP3A Expression by Hydroxymethylglutaryl Coenzyme A Inhibitors in Primary Cultured Human Hepatocytes

Abstract

ABSTRACT:The effects of treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin on the contents of cytochrome P450 mRNAs were examined in primary cultures of human hepatocytes prepared from three different livers. Treatment of 2-to 3-day-old human hepatocyte cultures with 3 ؋ 10 ؊5 M lovastatin, simvastatin, fluvastatin, or atorvastatin for 24 h increased the amounts of CYP2B6 and CYP3A mRNA by an average of 3.8-to 9.2-fold and 24-to 36-fold, respectively. In contrast, pravastatin treatment had no effect on the mRNA level of either CYP2B6 or CYP3A, although treatment with pravastatin did produce the expected compensatory increase in HMG-CoA reductase mRNA content, indicating effective inhibition of cholesterol biosynthesis. Although treatment with the active (؉), but not the inactive (؊), enantiomer of atorvastatin increased the amount of HMG-CoA reductase mRNA, treatment with each enantiomer significantly induced both CYP2B6 and CYP3A mRNA levels. Treatment of primary cultured rat hepatocytes with the atorvastatin enantiomers effectively increased the amount of CYP3A mRNA, but had no effect on CYP2B or CYP4A mRNA levels, in contrast to fluvastatin, which increased both. Findings for P450 proteins by Western blotting were consistent with the mRNA results. These findings indicate that the ability of a drug to inhibit HMG-CoA reductase activity does not predict its ability to produce P450 induction in primary cultured human hepatocytes, and demonstrate that some, but not all, of the effects of these drugs that occur in primary cultured rat hepatocytes are conserved in human hepatocyte cultures.Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase 2 ), also known as "statins", have achieved an important place in the arsenal of therapeutic agents available for the treatment of hypercholesterolemia, a major risk factor for the development of coronary artery disease, the leading cause of death in the United States. Five drugs of this class are currently approved for use in the United States, namely, lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin (Food and Drug Adminstration Orange Book; http://www.fda.gov/cder/ob/default.htm). In general, these drugs have proven to be safe and effective when taken over a period of years (Davidson, 2001), and additional therapeutic uses of these drugs are under investigation (White, 1999;Puddu et al., 2001;Whitfield, 2001).However, one precaution in the use of these drugs is that most of them have been shown to interact, in one manner or another, with the cytochrome P450 system of drug-metabolizing enzymes, thereby leading to the possibility for pharmacokinetic interactions with coadministered drugs. Thus, abundant information indicates that lovastatin, simvastatin, and atorvastatin interact with human CYP3A, both as substrates and inhibitors (Prueksaritanont et al., 1997;Beaird, 2000;Cohen et al., 2000;Farmer and Torre-Amione, 20...

Different anti-HCV profiles of statins and their potential for combination therapy with interferon

“…However, we found unexpectedly that PRV did not inhibit HCV RNA replication, whereas PRV inhibited HMG-CoA reductase as effectively as other statins possessing anti-HCV activity. Although PRV is a water-soluble reagent (others are lipophilic), we confirmed PRV did induce expression of HMG-CoA reductase by a positive feedback mechanism 18 and LST-1 was expressed in our cell culture system. These findings suggest the presence of a mechanism in which PRV's inhibition of HMG-CoA reductase does not cause the depletion of geranylgeranyl pyrophosphate.…”

“…Interestingly, it has been reported that PRV has a unique effect among statins on the induction of p450. 18 Therefore, further studies are needed to explain why PRV exhibits no anti-HCV activity.…”

“…18 OR6c cells were treated with statins in the same way as were the OR6 cells used to measure the anti-HCV activity of statins, except that sampling for RT-PCR was performed after 24 hours of statin treatment. All statins, including PRV, enhanced expression of the HMG-CoA reductase gene (Fig.…”

Human relevance framework for rodent liver tumors induced by the insecticide sulfoxaflor

“…Serum clinical chemistry values in rodents indicated that treatment with high doses of sulfoxafl or increased cholesterol. Although various classes of statins act diff erently, a common response is an increase in Cyp2b and Cyp4a gene expression and protein levels in the rodent liver (Kocarek and Reddy 1996), whereas sulfoxafl or did not exhibit any induction in Cyp4a transcript levels, and in many cases it decreased (LeBaron et al 2013). Overall, the lack of concordant localized periportal atypia and bile duct hyperplasia indicate the hepatic eff ects seen with sulfoxafl or administration are not consistent with known eff ects of statins in the rodent liver.…”

Efeitos de hipolipemiantes sobre a expressão de CYP3A4 e CYP3A5 in vitro e in vivo

“…Como já previamente publicado (KUEHL et al, 2001;KOCAREK et al, 2002;ROUITS et al, 2003;XIE et al, 2004;SIEST et al, 2005, NEUVONEN et al, 2006KRAUSS, 2007, WANG et al, 2011, LAMBA et al, 2010, em nossas amostras há uma grande variabilidade interindividual na expressão …”