Mechanism of Hepatic Microsomal Oxidation of ll-Hydroxy-A8-tetrahydrocannabinol to ll-Oxo-A8-tetrahydrocannabinol. Evidence for Hydration of the Aldehyde Formed

Abstract

Hepatic microsomal oxidation of 1 l-hydroxy-A8-tetrahydrocannabinol (1 l-OH-A8-THC) to ll-oxo-A8-THC was investigated. Hepatic microsomes from mice, rats, guinea pigs and rabbits catalyzed the oxidation of ll-OH-A8-THC to ll-oxo-A8-THC together with the formation of dihydroxy-A8-THCs oxidized at the 7-position or at the pentyl side chain of 1 l-OH-A8-THC. ll-Oxo-A8-THC formed under oxygen-18 gas was analyzed by gas chromatography-mass spectrometry (GC-MS) indicating that molec ular oxygen was not significantly incorporated into the aldehyde formed. 11-Oxo-AS-THC formed from ll-l8OH-A8-THC (!80/160 = 0.81 - 1.05) was also found to lose oxy gen-18 from the molecule. These results suggest that ll-oxo-A8-THC is hydrated in the incubation mixture and the aldehyde oxygen is exchangeable with the oxygen ato m of water. When ll-oxo-A8-THC was incubated with hepatic microsomes and phosphate buffer containing H2I80 (44 atomo), GC-MS analysis indicated the incorporation o f oxygen-18 into the aldehyde recovered from the incubation mixture. The results suggest that the hepatic microsomes may facilitate the hydration of 11-oxo-A8-THC a nd exchange an oxygen atom of the aldehyde group with that of water in the incubation mixture. © 1992, The Pharmaceutical Society of Japan. All rights reserved.