Oh 178

Scheme 18

As more information becomes available, it is becoming increasingly probable that the contributions of AOX and xanthine oxidoreductase to the metabolism of drugs that incorporate aryl nitrogen-containing heterocycles have been largely unrecognized and underestimated. Aldehyde Dehydrogenases

The aldehyde dehydrogenases are members of a superfamily of pyridine nucleotide (NAD(P) + )-dependent oxido-reductases that catalyze the oxidation of aldehydes to carboxylic acids, are widely distributed in mammals, and are found in cytosol, mitochondria, and microsomes.

Seventeen genes have been identified in the human genome that code for aldehyde dehydrogenases, attesting to the importance of these enzymes to normal physiological function.

Aldehyde dehydrogenases can be placed in two broad categories: (1) those that are highly substrate-selective and are critical for normal development, and (2) those that are less substrate-selective and protect the organism from potentially toxic aldehydes contained in food or generated from xenobiotics.204 An example of aldehyde dehydrogenases that fall into the first category are those that oxidize retinal (68) to retinoic acid (69) (eqn [24]), a molecule important for growth and development.206

Aldehyde dehydrogenases that fall into the second category are almost invariably detoxifying. The most common example is the oxidation of alcohol-derived acetaldehyde to acetic acid. However, sometimes it is advantageous to inhibit their detoxifying effects. For example, inhibition of acetaldehyde oxidation by the administration of disulfiram (179) is a common treatment for alcohol abuse.207 In vivo, 179 is converted to diethylthiomethylcarbamate (180), the active inhibitor (eqn [52]). Inhibition results in potentially toxic levels of acetaldehyde upon ingestion of alcohol by the abuser.

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