Mechanism of the metabolism of 1,3-benzodioxoles to carbon monoxide.

Carbon monoxide is a minor product formed during the cytochrome P-450-catalyzed oxidation of 1,3-benzodioxoles. Studies with [2-13C]methylene 1,3-benzodioxoles established that the methylenic carbon of the 1,3-benzodioxole ring is the source of the carbon atom in the carbon monoxide, and an isotope effect of 1.7 to 2.0 was observed with [2-2H2]methylene derivatives. Incubations conducted in the presence of [18O]dioxygen and [18O]water showed that the oxygen atom in carbon monoxide arises from both oxygen and water. A mechanism consistent with these data has been proposed for carbon monoxide formation. It involves initial monooxygenation of the 1,3-benzodioxole to a 2-hydroxy derivative that subsequently forms a 2-hydroxyphenyl formate intermediate, which yields either carbon monoxide or formate. The proposed mechanism is discussed in terms of its possible relationship to the inhibitory activity of 1,3-benzodioxoles toward microsomal oxidation.