Mechanism of Hepatic Microsomal Oxidation of 11-Hydroxy-Δ⁸-tetra-hydrocannabinol to 11-Oxo-Δ⁸-tetrahydrocannabinol. Evidence for Hydration of the Aldehyde Formed

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Hepatic microsomal oxidation of 11-hydroxy-Δ⁸-tetrahydrocannabinol (11-OH-Δ⁸-THC) to 11-oxo-Δ⁸-THC was investigated. Hepatic microsomes from mice, rats, guinea pigs and rabbits catalyzed the oxidation of 11-OH-Δ⁸-THC to 11-oxo-Δ⁸-THC together with the formation of dihydroxy-Δ⁸-THCs oxidized at the 7-position or at the pentyl side chain of 11-OH-Δ⁸-THC. 11-Oxo-Δ⁸-THC formed under oxygen-18 gas was analyzed by gas chromatography-mass spectrometry (GC-MS) indicating that molecular oxygen was not significantly incorporated into the aldehyde formed. 11-Oxo-Δ⁸-THC formed from 11-¹⁸OH-Δ⁸-THC (¹⁸O/¹⁶O=0.81-1.05) was also found to lose oxygen-13 from the molecule. These results suggest that 11-oxo-Δ⁸-THC is hydrated in the incubation mixture and the aldehyde oxygen is exchangeable with the oxygen atom of water. When 11-oxo-Δ⁸-THC was incubated with hepatic microsomes and phosphate buffer containing H₂¹⁸O (44 atom%), GC-MS analysis indicated the incorporation of oxygen-18 into the aldehyde recovered from the incubation mixture. The results suggest that the hepatic microsomes may facilitate the hydration of 11-oxo-Δ⁸-THC and exchange an oxygen atom of the aldehyde group with that of water in the incubation mixture.