Hepatic organelle interaction. IV. Mechanism of succinate enhancement of formaldehyde accumulation from endoplasmic reticulum N-dealkylations.

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Abstract
Further evidence for organelle interaction during drug metabolism by the [rat] liver is presented. The apparent stimulation by succinate of formaldehyde accmulation in the medium, which was reported to occur with liver slices and homogenates and with mitochondria plus microsomes, was the result of succinate inhibition of mitochondrial aldehyde dehydrogenase. The mechanism of succinate inhibition is by reverse electron transport and an increase in the mitochondrial NADH to NAD+ ratio; the aldehyde dehydrogenase requires the oxidized form of the pyridine nucleotide as its cofactor. Studies on in vitro N-demethylation by liver microsomes and endoplasmic reticulum segments which cosediment with the mitochondria indicate that formaldehyde produced by the mixed function oxidase is handled differently from formaldehyde added to the medium. The latter is mainly retained in the medium containing 5 mM semicarbazide, while the generated formaldehyde is more than 50% consumed by the mitochondria. EM indicated that the microsomes and the endoplasmic reticulum fragments tend to align themselves close to the mitochondria when present in the same medium. Possibly formaldehyde released to the medium adjacent to the mitochondria, as by N-demethylation, is exposed to semicarbazide for shorter periods than that added directly to the medium. In agreement with this suggestion, complexing of formaldehyde with semicarbazide was observed spectroscopically not to be an extremely rapid reaction even at 37.degree. C. This is believed to be the reason for the greater extent of consumption of formaldehyde generated by the endoplasmic reticulum.