Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism.
Article Details
- CitationCopy to clipboard
Gates S, Miners JO
Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism.
Br J Clin Pharmacol. 1999 Mar;47(3):299-305.
- PubMed ID
- 10215755 [ View in PubMed]
- Abstract
AIMS: The plasma clearance of theobromine (TB; 3,7-dimethylxanthine) is known to be induced in cigarette smokers. To determine whether TB may serve as a model substrate for cytochrome P450 (CYP) 1A2, or possibly other isoforms, studies were undertaken to identify the individual human liver microsomal CYP isoforms responsible for the conversion of TB to its primary metabolites. METHODS: The kinetics of formation of the primary TB metabolites 3-methylxanthine (3-MX), 7-methylxanthine (7-MX) and 3,7-dimethyluric acid (3,7-DMU) by human liver microsomes were characterized using a specific hplc procedure. Effects of CYP isoform-selective xenobiotic inhibitor/substrate probes on each pathway were determined and confirmatory studies with recombinant enzymes were performed to define the contribution of individual isoforms to 3-MX, 7-MX and 3,7-DMU formation. RESULTS: The CYP1A2 inhibitor furafylline variably inhibited (0-65%) 7-MX formation, but had no effect on other pathways. Diethyldithiocarbamate and 4-nitrophenol, probes for CYP2E1, inhibited the formation of 3-MX, 7-MX and 3,7-DMU by approximately 55-60%, 35-55% and 85%, respectively. Consistent with the microsomal studies, recombinant CYP1A2 and CYP2E1 exhibited similar apparent Km values for 7-MX formation and CYP2E1 was further shown to have the capacity to convert TB to both 3-MX and 3,7-DMU. CONCLUSIONS: Given the contribution of multiple isoforms to 3-MX and 7-MX formation and the negligible formation of 3,7-DMU in vivo, TB is of little value as a CYP isoform-selective substrate in humans.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Theobromine Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Theobromine Cytochrome P450 2E1 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAminophyllineCarbamazepine The serum concentration of Aminophylline can be decreased when it is combined with Carbamazepine. BromotheophyllineCarbamazepine The serum concentration of Bromotheophylline can be decreased when it is combined with Carbamazepine. CaffeineCarbamazepine The serum concentration of Caffeine can be decreased when it is combined with Carbamazepine. DyphyllineCarbamazepine The serum concentration of Dyphylline can be decreased when it is combined with Carbamazepine. LomifyllineCarbamazepine The serum concentration of Lomifylline can be decreased when it is combined with Carbamazepine.