Effect of cytochrome P450 (CYP) inducers on caffeine metabolism in the rat.
Journal Title: Pharmacological Reports - Year 2007, Vol 59, Issue 3
Abstract
Our previous studies, carried out using rat cDNA-expressed cytochrome P450 (CYP) isoforms, liver microsomes and specific CYP inhibitors, showed that the 1-N- and 3-N-demethylation of caffeine at a therapeutic concentration was predominantly catalyzed by CYP1A2 and CYP2C, its 7-N-demethylation was governed by P450s of the CYP2C subfamily, while its 8-hydroxylation was specifically mediated by CYP1A2. The present study was aimed at corroborating the above-described results using another experimental model, i.e. a study of caffeine metabolism in the liver microsomes and specific CYP inducers. Animals received one of the following inducers: beta-naphthoflavone (100 mg/kg ip for 4 days), phenobarbital (10 mg/kg for 6 days or 100 mg/kg ip for 4 days), pregnenolone 16alpha-carbonitrile (100 mg/kg ip for 4 days) or 15% ethanol ( approximately 11 g/kg in drinking water for 6 days). Sixteen hours after the last dose of an inducer liver microsomes were prepared and the caffeine metabolism and CYP isoform activities (testosterone 2alpha-, 2beta-, 6beta-, 7alpha-, 16beta-hydroxylation and warfarin 7-hydroxylation) were investigated. beta-Naphthoflavone (mainly a CYP1A inducer and CYP2C11 inhibitor) potently accelerated the metabolism of caffeine, the effect on 7-N-demethylation being the weakest. Moreover, the influence of beta-naphthoflavone on caffeine metabolism was more potent at the substrate concentration of 100 muM than 800 muM, in particular in the case of 7-N-demethylation and 8-hydroxylation. Pregnenolone-16alpha-carbonitrile (mainly a CYP3A inducer and CYP2C11 inhibitor) moderately induced 8-hydroxylation only. Phenobarbital (an inducer of CYP2B and other CYPs and a CYP2C11 inhibitor) moderately stimulated the metabolism of caffeine, but practically did not affect 7-N-demethylation. Ethanol (mainly a CYP2E1 inducer) modestly increased the rates of the N-demethylation reactions. The presently obtained data confirm the pivotal role of CYP1A2 in the metabolism of caffeine, as well as the involvement of CYP3A in the 8-hydroxylation of caffeine and that of CYP2C11 in its 7-N-demethylation.
Authors and Affiliations
Marta Kot, Władysława Daniel
Keywords
Related Articles
- EP ID EP112928
- DOI -
- Views 116
- Downloads 0
Adenosine receptor antagonists intensify the benzodiazepine withdrawal signs in mice.
The aim of the present experiment was to assess the involvement of adenosine receptor antagonists in benzodiazepine (BDZ) withdrawal signs, observed as the seizure susceptibility in mice. The discontinuation of chronic t...
Investigation of allele and genotype frequencies of CYP2C9, CYP2C19 and VKORC1 in Iran.
Research has shown that there are significant ethnic variations in the frequency of highly functional mutations in genes coding for metabolic enzymes. However, few studies have examined the frequency distribution of majo...
New conjugates of muramyl dipeptide and nor-muramyl dipeptide linked to tuftsin and retro-tuftsin derivatives significantly influence their biological activity.
The synthesis and biological activity of new conjugates of muramyl dipeptide (MDP) and nor-muramyl dipeptide (nor-MDP) with tuftsin and retro-tuftsin derivatives containing isopeptide bond between ε-amino group of lysine...
Acquisition and expression of ethanol-induced conditioned place preference in mice is inhibited by naloxone.
The effects of opioid antagonists on conditioned reward produced by ethanol provide variable and sometimes conflicting results, especially in mice. In the present set of experiments, male C57BL/6 mice received 4 vehicle...
Dose-response relationship analysis of vigabatrin doses and their antinociceptive effects in the hot-plate test in mice.
This study was aimed at determining the analgesic effects of vigabatrin (VGB, a newer antiepileptic drug) in the acute thermal pain model (hot-plate test) in mice. Linear regression analysis was used to evaluate a dose-r...