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Abstract
1. The involvement of glutathione (GSH) and cytochrome P-450 in the conversion of theobromine to 6-amino-5-(N-methylformylamino)-1-methyluracil (3,7-DAU) and 3,7-dimethyluric acid (3,7-DMU) has been investigated in rat liver microsomal incubations.
2. The ratio of formation of 3,7-DAU to 3,7-DMU increased with increasing GSH concentration, reaching a maximum (approximately 12:1) at 2mm. For any given added GSH concentration the formation of 3,7-DAU plus 3,7-DMU remained constant.
3. 3,7-DAU and 3,7-DMU formation were increased approx. 12- and 1.6-fold in liver microsomes from rats treated with 3-methylcholanthrene and phenobarbitone, respectively. Cimetidine, metyrapone and SKF-525A each inhibited the conversion of theobromine to 3,7-DAU and 3,7-DMU.
4. Apparent Km and V,max values for the combined formation of 3,7-DAU and 3,7-DMU were the same in the absence and presence of GSH, 2mm.
5. l-Cysteine and N-acetyl-l-cysteine were as effective as GSH in causing a shift from 3,7-DMU to 3,7-DAU formation, but the non-thiol reducing agents ascorbic acid and α-tocopherol were ineffective.
6. Data are consistent with the hypothesis that 3,7-DAU and 3,7-DMU are derived from a common oxidized intermediate of theobromine, the formation of which is rate-limiting. The putative intermediate normally serves as a precursor to 3,7-DMU but in the presence of GSH. or some other cellular thiol, it may be reduced to give 3,7-DAU.
