title: Effects of unsaturated side-chain analogs of tetrahydrocannabinol on cytochromes P450.
abstract: The ability of unsaturated side-chain analogs of Delta(8)-tetrahydrocannabinol (THC) to selectively inactivate mouse hepatic cytochromes P450 3A11 and 2C29 was examined. THC side-chain analogs were preincubated with mouse hepatic microsomes and NADPH for various times before dilution and determination of Delta(9)-THC metabolism specific for P450s 3A11 and 2C29. THC-enyl analogs had little or no effect on P450 3A11 but inactivated P450 2C29 in a time-dependent manner, with approximately 50% inactivation observed after a 30-min preincubation. THC-ynyl analogs were less selective in their P450 inactivation but appeared to be more effective than their corresponding enyl analogs. THC-ynyl analogs inactivated P450s 3A11 and 2C29 in a time-dependent manner and could inactive 40-80% of their activities after a 30-min preincubation. The THC-ynyl analogs were nearly as effective as cannabidiol, a well-characterized inactivator of these mouse P450s. Despite their ability to inactivate P450 in vitro, neither the THC-enyl nor the THC-ynyl analogs were very effective after in vivo administration. Unsaturated side-chain THC analogs may be useful in the development of specific P450 inactivators.
authors.affiliation: Department of Cellular and Molecular Pharmacology and the Liver Center, University of California, San Francisco, CA 94143-0450, USA. lmb@itsa.ucsf.edu
authors.forename: L M
authors.initials: LM
authors.lastname: Bornheim
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D013759:Dronabinol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006213:Hallucinogens / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006213:Hallucinogens; C400322:cytochrome P-450 CYP2C subfamily; D013759:Dronabinol; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating