Narimatsu S, Matsubara K, Shimonishi T, Watanabe K, Yamamoto I, Yoshimura H
School of Pharmacy, Hokuriku University, Kanazawa, Japan.
Drug Metab Dispos. 1988 Jan-Feb;16(1):156-61.
Hepatic microsomes of the guinea pig converted delta 8-tetrahydrocannabinol (delta 8-THC) to various oxidized metabolites, including 7 alpha-hydroxy-delta 8-THC (7 alpha-OH-delta 8-THC), 7 beta-OH-delta 8-THC, and 7-oxo-delta 8-THC. The enzyme which mediates biotransformation of 7-OH-delta 8-THCs to 7-oxo-delta 8-THC was characterized in the present study. The oxidative activity was mainly located in microsomes. The microsomal reaction required NADPH and oxygen and showed an optimal pH around 7.5. The reaction was inhibited by beta-diethylaminoethyl diphenylpropylacetate (SKF 525-A), an inhibitor of cytochrome P-450, but not by pyrazole, a specific inhibitor of alcohol dehydrogenase. However, 7-oxo-delta 8-THC formation was not affected by carbon monoxide or by pretreatment of animals with cobaltous chloride (40 mg/kg, ip, once a day for 3 days). Atmospheric oxygen was incorporated into 7-oxo-delta 8-THC formed from 7 alpha-OH-delta 8-THC, but not into that from 7 beta-OH-delta 8-THC. Further, 7-oxo-delta 8-THC formed from 7 alpha-18OH-delta 8-THC released about half of 18O at the 7-position, whereas the 7-oxo metabolite from 7 beta-18OH-delta 8-THC lost little of the isotope at the 7 beta-position during the oxidative reaction. From these results, it is likely that hepatic microsomal monooxygenase (probably cytochrome P-450) plays a main role in the oxidation. In addition, mechanisms for 7-oxo-delta 8-THC formation from 7 alpha-OH-delta 8-THC or 7 beta-OH-delta 8-THC are different.
豚鼠的肝微粒体将δ8 - 四氢大麻酚（δ8 - THC）转化为多种氧化代谢产物，包括7α - 羟基 - δ8 - THC（7α - OH - δ8 - THC）、7β - OH - δ8 - THC和7 - 氧代 - δ8 - THC。本研究对介导7 - OH - δ8 - THC向7 - 氧代 - δ8 - THC生物转化的酶进行了表征。氧化活性主要位于微粒体中。微粒体反应需要NADPH和氧气，最适pH约为7.5。该反应被细胞色素P - 450抑制剂β - 二乙氨基乙基二苯基丙基乙酸酯（SKF 525 - A）抑制，但不被乙醇脱氢酶的特异性抑制剂吡唑抑制。然而，7 - 氧代 - δ8 - THC的形成不受一氧化碳影响，也不受用氯化钴（40 mg/kg，腹腔注射，每天一次，共3天）对动物进行预处理的影响。大气中的氧被掺入由7α - OH - δ8 - THC形成的7 - 氧代 - δ8 - THC中，但不掺入由7β - OH - δ8 - THC形成的7 - 氧代 - δ8 - THC中。此外，由7α - 18OH - δ8 - THC形成的7 - 氧代 - δ8 - THC在第7位释放约一半的18O，而由7β - 18OH - δ8 - THC形成的7 - 氧代代谢产物在氧化反应过程中在7β位几乎没有损失同位素。根据这些结果，肝微粒体单加氧酶（可能是细胞色素P - 450）可能在氧化过程中起主要作用。此外，由7α - OH - δ8 - THC或7β - OH - δ8 - THC形成7 - 氧代 - δ8 - THC的机制不同。
