Cytochrome P-450 isozymes in metabolic activation of delta 9-tetrahydrocannabinol by rat liver microsomes.

delta 9-Tetrahydrocannabinol (THC) was incubated with a reconstituted system consisting of dilauroylphosphatidylcholine, NADPH-cytochrome c reductase, cytochrome b5, and cytochrome P-450 (P-450) isozyme UT-2, UT-4, or UT-5, which was purified from liver microsomes of adult male rats. It was biotransformed by UT-2 to 11-OH-delta 9-THC and 3'-OH-delta 9-THC, and by UT-4 to 8 beta-OH-delta 9-THC and 11-OH-delta 9-THC. UT-5, however, showed only a little activity for 11-OH-delta 9-THC formation. Activity of the isozyme UT-2 for 11-OH-delta 9-THC formation from delta 9-THC was calculated to be 4.07 nmol/min/nmol P-450 while those of UT-2 for the formations of 16 alpha-OH-testosterone (16 alpha-OH-T), 2 alpha-OH-T, and androstenedione from testosterone were 14.7, 6.6, and 2.2 nmol/min/nmol P-450, respectively. Anti-P-450 UT-2 IgG fraction obtained from rabbit serum dose-dependently suppressed formations of 16 alpha-OH-T, 2 alpha-OH-T, and androstenedione from testosterone with liver microsomes of adult male rats. The antibody, in the amount that inhibited above 90% of 16 alpha-OH-T and 2 alpha-OH-T formations from testosterone, also reduced 80% of the microsomal formations of 11-OH-delta 9-THC and 3'-OH-delta 9-THC from delta 9-THC, as compared with control experiments using preimmune IgG fraction.(ABSTRACT TRUNCATED AT 250 WORDS)