Formation of Carbon Monoxide during Mouse Hepatic Microsomal Oxidative Metabolism of Cannabidiol ; Identification and Determination

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Carbon monoxide (CO) was generated in the process of hepatic microsomal oxidative metabolism of cannabidiol (CBD). After the generated CO was reduced to methane (CH_4) with a methanizer, CH_4 formed was determined by gas chromatography (GC) with a flame ionization detector. After oxidation with hopcalite, CO was also identified as CO_2 by gas chromatography/mass spectrometry (GC/MS). The reaction was NADPH-dependent and required molecular oxygen. It was inhibited by addition of some inhibitors of cytochrome P450-dependent monooxygenase. When CBD (191 μM) was incubated with hepatic microsomes of mice in the presence of an NADPH-generating system and oxygen, concentration of CO determined by GC was 4.7±0.5 ppm/nmol P450 in the incubation atmosphere. Pretreatment with phenobarbital (100 mg/kg, i.p. for 3 d) but not 3-methylcholanthrene (80 mg/kg, i.p.) increased the CO formation 78%, while pretreatment with cobaltous chloride (40 mg/kg, i.p. for 3 d) decreased the formation 56%. When CBD was incubated under oxygen-18 gas, molecular oxygen was not incorporated into the CO molecule. 8,9-Dihydro- and 1,2,8,9-tetrahydro-CBDs also produced CO to some extent, whereas CBD monomethyl- and dimethylethers reduced the ability to produce CO. In addition, cannabidivarin and olivetol produced CO, although none of Δ^9-tetrahydrocannabinol, cannabinol and d-limonene did. Thus, the resorcinol moiety of CBD is important for CO formation.
社団法人日本薬学会の論文
1995-04-15

Formation of Carbon Monoxide during Mouse Hepatic Microsomal Oxidative Metabolism of Cannabidiol ; Identification and Determination

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