Sex difference in induction of hepatic CYP2B and CYP3A subfamily enzymes by nicardipine and nifedipine in rats
Introduction
Calcium channel antagonists are widely used for the treatment of hypertension. However, there are many reports on clinical drug–drug interactions with the calcium channel antagonists Bertz and Granneman, 1997, Campana et al., 1996, Rosenthal and Ezra, 1995, Schlanz et al., 1991. As one of possible explanations for such clinical drug–drug interactions, inhibition of the cytochrome P450 (P450) activities by calcium channel antagonists has been suggested, because calcium channel antagonists including nicardipine (Nic) and nifedipine (Nif) have been demonstrated to show capacities for inhibiting the activities of CYP3A, CYP2C9, or CYP2D6 in human hepatocytes and liver microsomes Ma et al., 2000, Pichard et al., 1990. In addition, calcium channel antagonists have been reported to serve as inhibitors of P450 enzymes, especially CYP3A subfamily enzymes, in animals Mäenpää et al., 1989, Murray and Butler, 1996.
On the other hand, calcium channel antagonists have been also reported to promote the metabolism of several drugs in rats and to shorten the hexobarbital-sleeping time Koleva and Stoychev, 1993, Koleva and Stoychev, 1995. More recently, calcium channel antagonists such as nicardipine (Nic) and nifedipine (Nif) have been found to show capacities for inducing CYP3A and CYP2B subfamily enzymes in the rat liver Konno et al., 2003, Zangar et al., 1999 and in human hepatocytes (Drocourt et al., 2001). These reports suggest that induction of P450s by calcium channel antagonists is a cause of the drug–drug interactions.
As for the induction of hepatic CYP3A and CYP2B subfamily enzymes in rats, gender-related differences are known. CYP3A2 is induced in adult male rats but not in the females by dexamethasone Cooper et al., 1993, Mahnke et al., 1997. Likewise, the induction of CYP2B subfamily enzymes, including CYP2B1 and CYP2B2, by phenobarbital occurs preferentially in male rats Agrawal and Shapiro, 1996, Larsen et al., 1994, Shapiro et al., 1994. To date, however, study on a gender-related difference in calcium channel antagonist-mediated induction of hepatic CYP2B and CYP3A subfamily enzymes has not been performed.
In the present study, we examined the induction of hepatic CYP2B and CYP3A subfamily enzymes by Nic and Nif in male and female rats and demonstrated for the first time the sex difference in the calcium channel antagonist-mediated induction of the P450 enzymes.
Section snippets
Chemicals
Nicardipine hydrochloride (Nic) and nifedipine (Nif) were purchased from Wako (Osaka, Japan). These chemicals were the highest grade available.
Animals and treatment
Male and female of F344 rats (6 weeks of age) were purchased from Japan SLC Animal (Hamamatsu, Japan), kept in plastic cages in an air-conditioned room, and given MF diet (Oriental Yeast, Tokyo, Japan) and water ad libitum, and used at 7 weeks of age. Rats were treated per os with either Nic or Nif dissolved in corn oil as described previously (Konno et
Dose effects of Nic and Nif on the gene expression of hepatic CYP2B and CYP3A subfamily enzymes
Dose effects of Nic and Nif on hepatic gene expression of CYP2B and CYP3A subfamily enzymes, CYP2B1, CYP2B2, CYP3A1 CYP3A2, CYP3A9, and CYP3A18, in male and female rats were examined by the RT-PCR with the corresponding primer sets. We have previously reported that treatment of male rats with either Nic or Nif resulted in significant increases in hepatic expression levels of the CYP2B1, CYP2B2, CYP3A1, and CYP3A2 genes 24 h later (Konno et al., 2003). Therefore, in the present experiments, dose
Discussion
In the present study, we demonstrate for the first time the gender-related difference in the induction of CYP2B and CYP3A subfamily enzymes by Nic and Nif in rats and further indicate that these calcium channel antagonists show different specificities and sex dependencies in the induction of hepatic CYP2B and CYP3A subfamily enzymes. The present results from the RT-PCR and Western blot analyses indicate that Nic induces more efficiently CYP3A subfamily enzymes than CYP2B subfamily ones, whereas
Acknowledgements
This work was supported, in part, by a Grant-in-Aid from Scientific Research from the Japan Society for the Promotion of Science (M.D.).
References (31)
- et al.
Cytochrome P450 specificities of alkoxyresorufin O-dealkylation in human and rat liver
Biochem. Pharmacol.
(1994) - et al.
Regulation of two members of the steroid-inducible cytochrome P450 subfamily (3A) in rats
Arch. Biochem. Biophys.
(1993) - et al.
Effect of nifedipine, verapamil and diltiazem on the enzyme-inducing activity of phenobarbital and beta-naphthoflavone
Gen. Pharmacol.
(1995) - et al.
The induction of five rat hepatic P450 cytochromes by phenobarbital and similarly acting compounds is regulated by a sexually dimorphic, dietary-dependent endocrine factor that is highly strain specific
Arch. Biochem. Biophys.
(1994) - et al.
Protein measurement with the folin phenol reagent
J. Biol. Chem.
(1951) - et al.
Expression and inducibility of cytochrome P450 3A9 (CYP3A9) and other members of the CYP3A subfamily in rat liver
Arch. Biochem. Biophys.
(1997) - et al.
Gene expression of neurotrophins and their receptors in lead nitrate-induced rat liver hyperplasia
Biochem. Biophys. Res. Commun.
(2000) - et al.
Sexually dimorphic expression of rat CYP3A9 and CYP3A18 genes is regulated by growth hormone
Biochem. Biophys. Res. Commun.
(1998) - et al.
Growth hormone-dependent and -independent sexually dimorphic regulation of phenobarbital-induced hepatic cytochromes P450 2B1 and 2B2
Arch. Biochem. Biophys.
(1994) - et al.
Regulation of CYP3A9 gene expression by estrogen and catalytic studies using cytochrome P450 3A9 expressed in Escherichia coli
Arch. Biochem. Biophys.
(1997)
Phenobarbital induction of hepatic CYP2B1 and CYP2B2: pretranscriptional and post-transcriptional effects of gender, adult age, and phenobarbital dose
Mol. Pharmacol.
Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions
Clin. Pharmacokinet.
Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes
J. Pharmacol. Exp. Ther.
Clinically significant drug interactions with cyclosporin. An update
Clin. Pharmacokinet.
Hepatocarcinogenic heterocyclic aromatic amines that induce cytochrome P-448 isozymes, mainly cytochrome P-448H (P450 1A2), responsible for mutagenic activation of the carcinogens in rat liver
Carcinogenesis
Cited by (17)
Alterations of cytochrome P450 and the occurrence of persistent organic pollutants in tilapia caged in the reservoirs of the Iguaçu River
2018, Environmental PollutionCitation Excerpt :CYP3A activity and expression in the liver were higher in individuals from the SS reservoir than in those from other reservoirs, thus indicating a possible increase in the metabolism of hydrophobic compounds and steroid hormones. In mammals, CYP expression has been shown to be altered by a variety of compounds (Konno et al., 2004; Li et al., 2008; Zhou et al., 2013). The majority of the detected chemicals in the Iguaçu River were predominantly in the SS and SO reservoirs, the same sites where overexpression of CYP3A was found.
Selective induction of intestinal CYP3A23 by 1α,25-dihydroxyvitamin D<inf>3</inf> in rats
2006, Biochemical PharmacologyCitation Excerpt :The rat was selected as a model for humans because both species reportedly show marked preferential intestinal (compared to hepatic) VDR expression [11,13], which we confirmed (Fig. 4). CYP3A9 was selected as a comparator gene because it has been shown to be less sensitive than CYP3A23 to the effects of known CYP3A inducers (via PXR activation) in male rats [25,26] and, indeed, it appeared to be less responsive to 1,25(OH)2D3 treatment than CYP3A23 (Fig. 1). These observations are consistent with a recent report [27] where intestinal CYP3A9 mRNA was induced ∼1.7-fold 24 h after albeit a single higher dose (270 ng) than what we employed (100 ng).
Generation of specific antibodies and their use to characterize sex differences in four rat P450 3A enzymes following vehicle and pregnenolone 16α-carbonitrile treatment
2006, Archives of Biochemistry and BiophysicsGene expression profile of sex-linked metabolic enzyme in rats inhabiting dichlorodiphenyltrichloroethane (DDT)-sprayed areas of South Africa
2022, Japanese Journal of Veterinary Research