The aims for the continuation of this project are centered on the most significant findings of my previous study: That cannabidiol (CBD) treatment produces both inactivation and induction of specific mouse hepatic cytochrome P-450(P-450) isozymes, resulting in altered capacity for metabolism of CBD and other cannabinoids. These findings suggest important clinical pharmacological consequences, since an alteration P-450 will affect the metabolism of most drugs concurrently ingested with CBD (a major constituent of marijuana), resulting in either decreased or increased elimination of those drugs. Altered metabolism could also affect the pharmacological response to tetrahydrocannabinol (THC), whose actions are believed to be mediated by THC metabolites. This proposal is designed to identify the chemical determinants of CBD involved in the inactivation process, and will aim to elucidate the mechanism of CBD- mediated P-450 induction. Rat and mouse hepatic P-450 appear to be differentially inhibited by CBD, and since P-450 induction is often observed after P-450 inhibition, possible differences in the mechanisms of CBD-mediated inhibition and induction in the two species will be examined. Biochemical changes and alterations in the genetic regulation of P-450 isozymes affected by CBD will be assessed. Because changes in P-450 isozymes are expected to affect THC metabolism, THC metabolites found to be formed in altered quantities after CBD treatments will be chemically synthesized and tested for pharmacological effects. In addition, the effect of CBD treatment on the metabolism of THC and other compounds by brain P-450 will also be determined. Thus, the overall goals of this study are to determine the mechanisms involved in CBD-mediated P-450 inactivation and induction, as well as to assess the consequences of such P-450 alterations on THC metabolism and action.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004265-06
Application #
3209661
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1987-01-01
Project End
1992-12-31
Budget Start
1992-01-01
Budget End
1992-12-31
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Reid, M J; Bornheim, L M (2001) Cannabinoid-induced alterations in brain disposition of drugs of abuse. Biochem Pharmacol 61:1357-67
Reid, M J; Bornheim, L M (2001) The effects of phencyclidine pretreatment on cocaine-mediated hepatotoxicity in mice. Toxicol Appl Pharmacol 172:194-202
Bornheim, L M (2000) Effects of unsaturated side-chain analogs of tetrahydrocannabinol on cytochromes P450. Biochem Pharmacol 60:955-61
Jager, W; Correia, M A; Bornheim, L M et al. (1999) Ethynylestradiol-mediated induction of hepatic CYP3A9 in female rats: implication for cyclosporine metabolism. Drug Metab Dispos 27:1505-11
He, K; Bornheim, L M; Falick, A M et al. (1998) Identification of the heme-modified peptides from cumene hydroperoxide-inactivated cytochrome P450 3A4. Biochemistry 37:17448-57
Bornheim, L M (1998) Effect of cytochrome P450 inducers on cocaine-mediated hepatotoxicity. Toxicol Appl Pharmacol 150:158-65
Bornheim, L M; Grillo, M P (1998) Characterization of cytochrome P450 3A inactivation by cannabidiol: possible involvement of cannabidiol-hydroxyquinone as a P450 inactivator. Chem Res Toxicol 11:1209-16
Kim, K Y; Bornheim, L M (1997) Determination of esterase-catalyzed cocaine metabolite formation by high-performance liquid chromatography with ultraviolet detection. J Chromatogr Sci 35:287-90
Jaeger, W; Benet, L Z; Bornheim, L M (1996) Inhibition of cyclosporine and tetrahydrocannabinol metabolism by cannabidiol in mouse and human microsomes. Xenobiotica 26:275-84
Bornheim, L M; Kim, K Y; Li, J et al. (1995) Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain. Drug Metab Dispos 23:825-31

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