The effect of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and newer antidepressant drugs on the activity and level of rat CYP3A
Introduction
Among CYP3A isoforms, human CYP3A4 and rat CYP3A2 (male-dominant) belong to the main constitutive enzymes expressed in the liver. These isoforms are predominantly expressed in the liver (Komori and Oda, 1994), but they have also been found in the intestine, kidneys, lungs, brain and leukocytes (Watkins, 1992, Debri et al., 1995, Wang et al., 1996). The CYP3A subfamily is characterized by its ability to utilize a wide spectrum of substrates being both small molecules, such as paracetamol and large ones like cyclosporin. The CYP3A substrates are endogenous substances (e.g. steroids) or xenobiotics (e.g. drugs such as psychotropics, carbamazepine and calcium antagonists). 6β-Hydroxylation of cortisol in humans and 2β- and 6β-hydroxylation of testosterone in rats are used as marker reactions for studying CYP3A activities (Gibson et al., 2002).
The CYP3A expression is under physiological and environmental influence. Hormonal status is of great importance with a specific secretion of growth hormone and some steroids (corticosterone, hydrocortisone, testosterone) up-regulating it on the one hand and triiodothyronine and interleukins IL-1, IL-2 and IL-6 down-regulating it on the other (Waxman et al., 1995, Anderson et al., 1998, Liddle et al., 1998, Pascussi et al., 2000c, Sunman et al., 2004). It has been shown that glucocorticoid receptor (GR), pregnane X receptor (PXR), constitutive androstane receptor (CAR) and vitamin D receptor (VDR) play an important role in the regulation of CYP3A genes (Honkakoski and Negishi, 2000, Honkakoski et al., 2001, Quatrochi and Guzelian, 2001, Gibson et al., 2002, Burk and Wojnowski, 2004). Both PXR and CAR act as dimers with retinoid acid X receptor (RXR). GR may contribute to CYP3A induction via direct or indirect molecular mechanism, including functional cross talk between GR-, PXR- and CAR-signaling pathways (Zhang et al., 1999, Pascussi et al., 2000a, Pascussi et al., 2000b, Pascussi et al., 2003).
Administration of antidepressants to patients for months or years creates conditions for their interference with different kinds of proteins, such as receptors and enzymes. The literature data show that antidepressants are substrates of cytochrome P-450, mainly of CYP2D6 and CYP3A4. Some of them are also inhibitors of those enzymes, e.g. fluoxetine and paroxetine inhibit CYP2D6, fluvoxamine inhibits CYP1A2 (Crewe et al., 1992, Brøsen et al., 1993, Jeppesen et al., 1996), while nefazodone blocks CYP3A4 (von Moltke et al., 1999) in humans. Moreover, fluoxetine and fluvoxamine moderately inhibit CYP3A4 (Preskorn, 1997, Sproule et al., 1997).
However, there is only a few data on the effect of those drugs administered in clinical conditions (or simulating clinical conditions) on the activity of cytochrome P-450. It has been shown that chronic treatment with pharmacological doses of tricyclic antidepressants (TADs), selective serotonin reuptake inhibitors (SSRIs) and nefazodone decreased, while mirtazapine increased the activity of CYP2D in the rat liver (Daniel and Netter, 1992, Daniel et al., 2002). Their effect on other CYP isoforms is less known. Imipramine given at high daily doses (100 mg kg− 1 p.o. once daily) for 5 days to rats increased the rates of CYP3A specific reactions, i.e. 2β- and 6β-hydroxylation of testosterone (Masubuchi et al., 1995), but the effect of chronic administration of pharmacological doses of imipramine or other antidepressants on that enzyme has not been investigated so far. Warrington (1992) suggested the induction of CYP by sertraline, expressed as an increase in antipyrine clearance by the antidepressant, the former drug being metabolized by many CYP isoforms (CYP3A4, CYP1A2, and CYP2C9).
On the other hand, the possibility of forming CYP-reactive metabolite complexes had been shown at high concentrations (100–200 μM) of some TADs and fluoxetine in vitro during their prolonged incubation in rat liver microsomes, indicating the involvement of CYP3A, CYP2C11 and CYP2A (Murray and Field, 1992, Bensoussan et al., 1995, McNeil and Murray, 1996, Murray and Murray, 2003). But it is not known whether the above mechanism can produce an inhibitory effect on CYP3A in vivo when animals are treated with pharmacological doses of antidepressants producing lower drug concentrations.
The aim of our study was to investigate the influence of 1-day and 2-week treatment with pharmacological doses of antidepressants (TADs, SSRIs, and the novel antidepressants nefazodone and mirtazapine) on the activity and protein level of CYP3A in liver microsomes (ex vivo study), which has not been done yet in either humans or rats. We also examined in our study the direct interaction of antidepressants with rat CYP3A in vitro (binding with cytochrome protein, which had been studied in humans, but not in rats) to show any possible effects of antidepressants on rat CYP3A, as well as differences in their direct effect on human and rat CYP3A. The obtained results indicate drug-dependent changes in the activity of rat CYP3A produced by antidepressants via different mechanisms.
Section snippets
Drugs and chemicals
Imipramine hydrochloride was provided by Polfa (Jelenia Góra, Poland), amitriptyline by H. Lundbeck A/S (Copenhagen, Denmark), while clomipramine was from RBI (Natick, MA, USA) and desipramine from Ciba-Geigy (Wehr, Germany). Fluoxetine hydrochloride was purchased from Eli Lilly (Indianapolis, IN, USA) and sertraline hydrochloride from Pfizer Corp. (Brussels, Belgium). Mirtazapine hydrochloride was donated by Organon (The Netherlands) and nefazodone by Bristol–Myers Squibb International, Ltd.
Model I
Some of the investigated antidepressant drugs added to liver microsomes of control rats inhibited the rate of 2β- and 6β-hydroxylation of testosterone (Table 1). Fig. 1, Fig. 2, Fig. 3 show examples of the Dixon plots obtained in our studies, which served as a basis for calculation of Ki constants. The obtained Ki values indicated that nefazodone, the SSRIs fluoxetine and sertraline, and clomipramine were the most potent inhibitors of the studied reactions (Ki < 100 μM), while other tricyclic
Discussion
Using three different experimental models, we tried to search for any possible mechanisms of antidepressant interactions with CYP3A. Each model could potentially discover a different mechanism: Model I (antidepressant added in vitro) – a direct effect of drug on CYP3A via binding to the enzyme; Model II (1-day treatment) – inactivation by reactive metabolites; Model III (chronic treatment) – influence on enzyme regulation, e.g. induction. The effects of antidepressants observed in Models II and
Acknowledgement and funding
This study was supported by grant no. 4 PO5F 010 15 from the State Committee for Scientific Research (KBN, Warszawa, Poland) and by the statutory funds of the Institute of Pharmacology, Polish Academy of Sciences.
References (51)
- et al.
Particular ability of cytochromes P450 3A to form inhibitory P450–iron–metabolite complexes upon metabolic oxidation of aminodrugs
Biochem. Pharmacol.
(1995) - et al.
Fluvoxamine is a potent inhibitor of cytochrome P4501A2
Biochem. Pharmacol.
(1993) - et al.
The influence of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics of thioridazine and its metabolites: in vitro and in vitro studies
Exp. Toxic. Pathol.
(1999) - et al.
The influence of selective serotonin reuptake inhibitors on the plasma and brain pharmacokinetics of the simplest phenothiazine neuroleptic promazine in the rat
Eur. Neuropsychopharmacol.
(1999) - et al.
Distribution and induction of CYP3A1 and CYP3A2 in rat liver and extrahepatic tissues
Biochem. Pharmacol.
(1995) - et al.
Inhibition of microsomal cytochromes P450 in rat liver by the tricycle antidepressant drug desipramine and its primary oxidized metabolites
Biochem. Pharmacol.
(1996) - et al.
Inhibition and metabolite complexation of rat hepatic microsomal cytochrome P450 by tricyclic antidepressants
Biochem. Pharmacol.
(1992) - et al.
Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes
Biochem. Biophys. Res. Commun.
(2000) - et al.
The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors
Biochim. Biophys. Acta.
(2003) - et al.
Covalent alteration of the CYP3A4 active site: evidence for multiple substrate binding domains
Arch. Biochem. Biophys.
(2001)
Regulation of testosterone hydroxylation by rat liver microsomal cytochrome P-450
Arch. Biochem. Biophys.
cDNA cloning of a novel CYP3A from rat brain
Biochem. Biophys. Res. Commun.
Drug metabolism by cytochrome P450 in the liver and small bowel
Gastroenterol. Clin. North Am.
Rat pregnane X receptor: molecular cloning, tissue distribution and xenobiotic regulation
Arch. Biochem. Biophys.
Effect of androgen administration during puberty on hepatic CYP2C11, CYP3A, and CYP2A1 expression in adult female rats
Drug Metab. Dispos.
Cytochrome P450 3A and their regulation
Naunyn-Schmiedeberg's Arch. Pharmacol.
The effect of selective re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes
Br. J. Clin. Pharmacol.
In vitro and in vitro studies on the disposition of mirtazapine in humans
Clin. Drug Investig.
Alteration of cytochrome P-450 by prolonged administration of imipramine and/or lithium to rats
Naunyn-Schmiedeberg's Arch. Pharmacol.
Cerebral pharmacokinetics of imipramine in rats after single and multiple dosages
Naunyn-Schmiedeberg's Arch. Pharmacol.
Pharmacokinetics and metabolism of thioridazine during co-administration of tricyclic antidepressants
Br. J. Pharmacol.
The effect of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics and metabolism of perazine in the rat
J. Pharm. Pharmacol.
Inhibition and possible induction of rat CYP2D after short- and long-term treatment with antidepressants
J. Pharm. Pharmacol.
Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man
Xenobiotica
Pharmacokinetic and pharmacodynamic evaluation of the inhibition of alprazolam by citalopram and fluoxetine
J. Clin. Psychopharmacol.
Cited by (45)
The role of the dorsal noradrenergic pathway of the brain (locus coeruleus) in the regulation of liver cytochrome P450 activity
2015, European Journal of Pharmacology