Monkey liver cytochrome P450 2C9 is involved in caffeine 7-N-demethylation to form theophylline.

Article Details

Citation

Copy to clipboard

Utoh M, Murayama N, Uno Y, Onose Y, Hosaka S, Fujino H, Shimizu M, Iwasaki K, Yamazaki H

Monkey liver cytochrome P450 2C9 is involved in caffeine 7-N-demethylation to form theophylline.

Xenobiotica. 2013 Dec;43(12):1037-42. doi: 10.3109/00498254.2013.793874. Epub 2013 May 16.

PubMed ID

23679834 [ View in PubMed

]

Abstract

Caffeine (1,3,7-trimethylxanthine) is a phenotyping substrate for human cytochrome P450 1A2. 3-N-Demethylation of caffeine is the main human metabolic pathway, whereas monkeys extensively mediate the 7-N-demethylation of caffeine to form pharmacological active theophylline. Roles of monkey P450 enzymes in theophylline formation from caffeine were investigated using individual monkey liver microsomes and 14 recombinantly expressed monkey P450 enzymes, and the results were compared with those for human P450 enzymes. Caffeine 7-N-demethylation activity in microsomes from 20 monkey livers was not strongly inhibited by alpha-naphthoflavone, quinidine or ketoconazole, and was roughly correlated with diclofenac 4'-hydroxylation activities. Monkey P450 2C9 had the highest activity for caffeine 7-N-demethylation. Kinetic analysis revealed that monkey P450 2C9 had a high Vmax/Km value for caffeine 7-N-demethylation, comparable to low Km value for monkey liver microsomes. Caffeine could dock favorably with monkey P450 2C9 modeled for 7-N-demethylation and with human P450 1A2 for 3-N-demethylation. The primary metabolite theophylline was oxidized to 8-hydroxytheophylline in similar ways by liver microsomes and by recombinant P450s in both humans and monkeys. These results collectively suggest a high activity for monkey liver P450 2C9 toward caffeine 7-N-demethylation, whereas, in humans, P450 1A2-mediated caffeine 3-N-demethylation is dominant.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Caffeine	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate	Details