Cytochrome P-450 isozymes involved in the oxidative metabolism of Δ⁹-tetrahydrocannabinol by liver microsomes of adult female rats

Oxidative metabolism of Δ⁹-tetrahydrocannabinol (THC) by liver microsomes was studied in female rats. Δ⁹-THC was mainly biotransformed to 11-hydroxy-Δ⁹-THC (11-OH-Δ⁹-THC) and 9α, 10α-epoxy-hexahydrocannabinol (EHHC) by liver microsomal fraction of adult female rat. Two isozymes of cytochrome P-450 (P-450) [F-1 (IIC6) and F-2 (IIC12)] were purified from liver microsomes of female rats and oxidation activities toward Δ⁹-THC were assessed in the reconstituted system containing NADPH-P-450 reductase and cytochrome b₅. P-450 F-1 showed considerable activity toward 11-OH-Δ⁹-THC formation (10.62 nmol/min/nmol of P-450), whereas P-450 F-2 did not show any activity toward Δ⁹-THC oxidation under the conditions used. Preincubation of microsomes with antiserum against P-450 F-1 obtained from rabbits caused a marked decrease in 11-OH-Δ⁹-THC formation, whereas antiserum against P-450 F-2 did not exhibit any inhibitory effect on the oxidation of Δ⁹-THC by liver microsomes of adult female rats. Further, antiserum against P-450 F-1 or F-2 did not affect the microsomal formation of 9α, 10α-EHHC from Δ⁹-THC. These results indicate that P-450 F-1 and its immunochemically related P-450 isozyme(s) play important roles in the formation of an active metabolite, 11-OH-Δ⁹-THC, from Δ⁹-THC by liver microsomes of adult female rats.