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Relative contribution of rat cytochrome P450 isoforms to the metabolism of caffeine: the pathway and concentration dependence.
Biochem Pharmacol. 2008 Apr 01; 75(7):1538-49.BP

Abstract

The aim of the present study was to estimate the relative contribution of rat P450 isoforms to the metabolism of caffeine and to assess the usefulness of caffeine as a marker substance for estimating the activity of P450 in rat liver and its potential for pharmacokinetic interactions in pharmacological experiments. The results obtained using rat cDNA-expressed P450s indicated that 8-hydroxylation was the main oxidation pathway of caffeine (70%) in the rat. CYP1A2 was found to be a key enzyme catalyzing 8-hydroxylation (72%) and substantially contributing to 3-N-demethylation (47%) and 1-N-demethylation (37.5%) at a caffeine concentration of 0.1mM (relevant to "the maximum therapeutic concentration in humans"). Furthermore, CYP2C11 considerably contributed to 3-N-demethylation (31%). The CYP2C subfamily (66%) - mainly CYP2C6 (27%) and CYP2C11 (29%) - played a major role in catalyzing 7-N-demethylation. At higher substrate concentrations, the contribution of CYP1A2 to the metabolism of caffeine decreased in favor of CYP2C11 (N-demethylations) and CYP3A2 (mainly 8-hydroxylation). The obtained results were confirmed with liver microsomes (inhibition and correlation studies). Therefore, caffeine may be used as a marker substance for assessing the activity of CYP1A2 in rats, using 8-hydroxylation (but not 3-N-demethylation-like in humans); moreover, caffeine may also be used to simultaneously, preliminarily estimate the activity of CYP2C using 7-N-demethylation as a marker reaction. Hence caffeine pharmacokinetics in rats may be changed by drugs affecting the activity of CYP1A2 and/or CYP2C, e.g. by some antidepressants.

Authors+Show Affiliations

Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.No affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18279840

Citation

Kot, Marta, and Władysława A. Daniel. "Relative Contribution of Rat Cytochrome P450 Isoforms to the Metabolism of Caffeine: the Pathway and Concentration Dependence." Biochemical Pharmacology, vol. 75, no. 7, 2008, pp. 1538-49.
Kot M, Daniel WA. Relative contribution of rat cytochrome P450 isoforms to the metabolism of caffeine: the pathway and concentration dependence. Biochem Pharmacol. 2008;75(7):1538-49.
Kot, M., & Daniel, W. A. (2008). Relative contribution of rat cytochrome P450 isoforms to the metabolism of caffeine: the pathway and concentration dependence. Biochemical Pharmacology, 75(7), 1538-49. https://doi.org/10.1016/j.bcp.2007.12.017
Kot M, Daniel WA. Relative Contribution of Rat Cytochrome P450 Isoforms to the Metabolism of Caffeine: the Pathway and Concentration Dependence. Biochem Pharmacol. 2008 Apr 1;75(7):1538-49. PubMed PMID: 18279840.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Relative contribution of rat cytochrome P450 isoforms to the metabolism of caffeine: the pathway and concentration dependence. AU - Kot,Marta, AU - Daniel,Władysława A, Y1 - 2008/01/05/ PY - 2007/11/08/received PY - 2007/12/19/revised PY - 2007/12/21/accepted PY - 2008/2/19/pubmed PY - 2008/4/9/medline PY - 2008/2/19/entrez SP - 1538 EP - 49 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 75 IS - 7 N2 - The aim of the present study was to estimate the relative contribution of rat P450 isoforms to the metabolism of caffeine and to assess the usefulness of caffeine as a marker substance for estimating the activity of P450 in rat liver and its potential for pharmacokinetic interactions in pharmacological experiments. The results obtained using rat cDNA-expressed P450s indicated that 8-hydroxylation was the main oxidation pathway of caffeine (70%) in the rat. CYP1A2 was found to be a key enzyme catalyzing 8-hydroxylation (72%) and substantially contributing to 3-N-demethylation (47%) and 1-N-demethylation (37.5%) at a caffeine concentration of 0.1mM (relevant to "the maximum therapeutic concentration in humans"). Furthermore, CYP2C11 considerably contributed to 3-N-demethylation (31%). The CYP2C subfamily (66%) - mainly CYP2C6 (27%) and CYP2C11 (29%) - played a major role in catalyzing 7-N-demethylation. At higher substrate concentrations, the contribution of CYP1A2 to the metabolism of caffeine decreased in favor of CYP2C11 (N-demethylations) and CYP3A2 (mainly 8-hydroxylation). The obtained results were confirmed with liver microsomes (inhibition and correlation studies). Therefore, caffeine may be used as a marker substance for assessing the activity of CYP1A2 in rats, using 8-hydroxylation (but not 3-N-demethylation-like in humans); moreover, caffeine may also be used to simultaneously, preliminarily estimate the activity of CYP2C using 7-N-demethylation as a marker reaction. Hence caffeine pharmacokinetics in rats may be changed by drugs affecting the activity of CYP1A2 and/or CYP2C, e.g. by some antidepressants. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/18279840/Relative_contribution_of_rat_cytochrome_P450_isoforms_to_the_metabolism_of_caffeine:_the_pathway_and_concentration_dependence_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(08)00007-5 DB - PRIME DP - Unbound Medicine ER -