Effect of short- and long-term treatment with antidepressant drugs on the activity of rat CYP2A in the liver.
Journal Title: Pharmacological Reports - Year 2005, Vol 57, Issue 6
Abstract
The aim of the present study was to investigate the influence of tricyclic antidepressants (TADs: imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2A measured as a rate of testosterone 7alpha-hydroxylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally (ip) for one day or two weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg/kg ip; desipramine, fluoxetine, sertraline 5 mg/kg ip; mirtazapine 3 mg/kg ip), in the absence of the antidepressants in vitro. Most of the investigated drugs directly inhibited the CYP2A activity when added in vitro to control liver microsomes. Their inhibitory effects were strong (clomipramine, fluoxetine and desipramine: K(i) = 15, 20 and 25 muM, respectively), moderate (sertraline and imipramine: K(i) = 50 and 75 muM, respectively) or weak (amitriptyline, nefazodone and mirtazapine: K(i) = 107, 127 and 250 muM, respectively). A one-day (i.e. 24-h) exposure to the investigated antidepressant drugs did not produce any significant changes in the rate of 7alpha-hydroxylation of testosterone in the rat liver microsomes, while chronic treatment with clomipramine or sertraline significantly increased the activity of CYP2A, which suggests enzyme induction. In summary, two different mechanisms of the antidepressant-CYP2A interaction have been found in rat liver: 1) the direct inhibition of CYP2A by most of the investigated TADs and SSRIs; 2) the in vivo weak induction of CYP2A by clomipramine and sertraline. This observation may be important to the interpretation of the results of pharmacological tests carried out on rats. It seems of primary importance to determine whether the influence of antidepressants on CYP2A6 in humans is analogous as on CYP2A1/2 in rats.
Authors and Affiliations
Anna Haduch, Jacek Wójcikowski, Władysława Daniel
Keywords
Related Articles
- EP ID EP83598
- DOI -
- Views 104
- Downloads 0
Effect of mirtazepine on the CYP2D activity in the primary culture of rat hepatocytes.
Our previous studies carried out on rats showed that mirtazapine given intraperitoneally at a dose of 3 mg/kg, twice a day for two weeks, increased the activity of CYP2D measured as ethylmorphine O-deethylation in liver...
Chronic ecstasy use increases neurotrophin-4 gene expression and protein levels in the rat brain.
Ecstasy is a widely abused psychoactive recreational drug that is known to induce neuroplastic effects. The molecular basis of addiction remains poorly understood, but diverse lines of evidence suggest that neurotrophins...
Effect of lipopolysaccharide and antidepressant drugs on glucocorticoid receptor-mediated gene transcription.
It has been hypothesized that pro-inflammatory response and hyperactivity of hypothalamic-pituitary-adrenocortical axis (HPA) are involved in the pathogenesis of depression. Hyperactivity of HPAaxis results probably from...
Effect of prior stress on interleukin-1β and HPA axis responses to acute stress.
Interleukin-1β (IL-1β) level is modulated during multiple stress reactions both in brain structures involved in hypothalamic-pituitary-adrenal (HPA) axis regulation and peripheral systems. Multiple distinct stressors ind...
Gender and the endothelium.
The understanding of the basis of gender differences in vascular function is of critical importance to establish gender targeted interventions in cardiovascular medicine. In this review we concentrate on the central role...