Caffeine 7-N-demethylation and C-8-oxidation mediated by liver microsomal cytochrome P450 enzymes in common marmosets.
作者： Shotaro Uehara , Yasuhiro Uno , Takashi Inoue , Takako Suzuki , Masahiro Utoh
DOI: 10.3109/00498254.2015.1096980
关键词: Caffeine 、 Hydroxylation 、 Ketoconazole 、 Pharmacology 、 Cytochrome P450 、 Demethylation 、 Microsome 、 Biology 、 Enzyme 、 Marmoset
摘要: 1. 3-N-Demethylation of caffeine (1,3,7-trimethylxanthine) is mediated by human cytochrome P450 1A2, whereas 7-N-demethylation and C-8-hydroxylation are reportedly catalyzed monkey 2C9 rat respectively. 2. Roles marmoset enzymes in oxidation were investigated using nine liver microsomes 14 recombinantly expressed enzymes. 3. Predominant activities moderately (r = 0.78, p < 0.05) highly (r = 0.82, p < 0.01) correlated with midazolam 1'-hydroxylation activities, respectively, while the former was not strongly affected ketoconazole or α-naphthoflavone. 4. Caffeine inhibited activated α-naphthoflavone, suggesting main involvements 3As. 5. Recombinant 3As had high Vmax/Km values for C-8-hydroxylation, comparable to Km microsomes. Marmoset 1As efficiently 3-N-demethylation apparently lower than those 6. These results collectively suggest active 3A toward 8-hydorxylaiton involvement multiple isoforms including 1A 7-N- 3-N-demethylations livers. P450s have slightly different properties regarding metabolic pathways.
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