Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms

doi:10.1016/0006-2952(92)90282-N

Biochemical Pharmacology

Volume 43, Issue 2, 22 January 1992, Pages 225-235

https://doi.org/10.1016/0006-2952(92)90282-N Get rights and content

Abstract

Primary steps in the metabolism of caffeine and theophylline are cleavage of methyl groups and/or hydroxylation at position 8, mediated by cytochromes P450. V79 Chinese hamster cells genetically engineered for stable expression of single forms of rat cytochromes P450IA1, P450IA2 and P450IIBI and human P450IA2 and rat liver epithelial cells expressing murine P450IA2 were used to overcome problems arising in the proper allocation of metabolic pathways to specific isoforms by conventional techniques. These cell lines were exposed to caffeine and/or theophylline, and concentrations of metabolites formed in the medium were determined by HPLC. Caffeine was metabolized by human, rat and murine P450IA2, resulting in the formation of four primary demethylated and hydroxylated metabolites. However, there were differences in the relative amounts of the metabolites. The human and the mouse P450IA2 isoforms predominantly mediated 3-demethylation of caffeine. The rat cytochrome P450IA2 mediated both 3-demethylation and 1-demethylation of caffeine to a similar extent. Theophylline was metabolized mainly via 8-hydroxylation. All cell lines tested were able to carry out this reaction, with highest activities in cell lines expressing rat or human P450IA2, or rat P450IA1. These results support the hypothesis that caffeine plasma clearance is a specific in vivo probe for determining human P450IA2 activity.

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Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms

Abstract

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

J Biol Chem

Biochem Pharmacol

Human cytochrome P450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines

Activation of promutagens by human cDNA-expressed cytochrome P450s

Mutat Environ

4-Quinolones inhibit biotransformation of caffeine

Eur J Clin Pharmacol

Verapamil-induced inhibition of theophylline in healthy humans

Pharmacol Toxicol

Biotransformation of caffeine by microsomes

Evidence for the involvement of several cytochromes P-450 in the first steps of caffeine metabolism by human liver microsomes

Drug Metab Dispos

Biotransformation of caffeine, paraxanthine, theophylline, ande theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes

Drug Metab Dispos

Quinolone inhibition of cytochrome P-450-dependent caffeine metabolism in human liver microsomes

Drug Metab Dispos

Theophylline and caffeine metabolism in man

Comparison of caffeine metabolism by slices, microsomes and hepatocyte cultures from adult human liver

Xenobiotica

Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in man

Br J Clin Pharmacol

In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes

Antimicrob Agents Chemother

Human cytochrome P450_PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines