Enzymatic oxidation of 7-hydroxylated delta 8-tetrahydrocannabinol to 7-oxo-delta 8-tetrahydrocannabinol by hepatic microsomes of the guinea pig.
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.
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D013759:Dronabinol / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006168:Guinea Pigs; D006900:Hydroxylation; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D011335:Proadifen / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism
D013759:Dronabinol; D011335:Proadifen