Primary amine oxidations
Primary amines found in sulphonamides and sulphones can be metabolized to hydroxylamines and their toxicity hinges on these pathways.The hydroxylamines formed are often reactive and although they can be stabilized by glutathione (GSH) and other cellular antioxidants, they can spontaneously oxidize in the presence of oxygen to nitroso and then nitro-derivatives. The nitro forms are usually stable, but are vulnerable to reductive metabolism that drives the process shown in Figure 3.21 in the opposite direction. Secondary amines can also be oxidized to hydroxylamines.
Oxidation of alcohol and aldehydes
Although CYP2E1 is induced by ethanol, the vast majority of ethanol clearance (90 per cent) is normally by oxidation to acetaldehyde by another group of enzymes, the alcohol dehydrogenases (ADHs). These enzymes are found in the cytoplasm and they are NAD+ dependent zinc metalloenzymes. They form NADH from NAD+ in the process of alcohol oxidation. There are five classes of ADH isoforms. Class I (ADH1, ADH2, ADH3) isoforms have a high affinity for ethanol and can be blocked by pyrazoles. Classes II and III are more suited to the metabolism of longer chain alcohols and cannot be blocked by pyrazole.
Aldehydes are formed from many reactions in cells, but they are oxidized to their corresponding carboxylic acid by several enzyme systems, including aldehyde dehydrogenase ALDH’s, xanthine oxidase and aldehyde oxidase. These enzymes are usually detoxifying, as many aldehydes, such as formaldehyde, are cytotoxic by-products of CYP and other oxidative reactions. Of the three aldehyde dehydrogenase classes, two are relevant to alcohol metabolism. Class I are found in the liver cytosol and specialize in acetaldehyde. Class II ALDHs are found in the liver and kidney mitochondria and metabolize acetaldehyde and several other substrates.
Monoamine oxidase (MAO)
Yet another important oxidative enzyme system that processes endogenous and exogenous substrates is monoamine oxidase (MAO), which exists in two isoforms, MAO A and MAO B. Both are found in the outer membrane of mitochondria in virtually all tissues. They have evolved to become two separate enzymes with similar functions and they originate from different genes in man. They use FAD as a cofactor and are capable of oxidizing a very wide variety of endogenous biogenic amines as well as primary, secondary and tertiary xenobiotic amines. They accomplish their removal of amine groups through an initial reductive half-reaction, followed by an oxidation half-reaction. The reductive half oxidizes the amine and the FAD is reduced. The second half of the process involves the use of oxygen to reoxidize the FAD, leaving hydrogen peroxide and an aldehyde as products. Clorgyline blocks MAO A, whilst deprenyl is a potent inhibitor of MAO B. In the 1960s, irreversible MAO inhibitors were used as antidepressants, aimed at increasing biogenic amine levels. Unfortunately, they could cause hypertensive crises (sufficient to cause a stroke) through ingestion of other amines, such as tyramine from cheese and a long list of other foods. MAO inhibitors are still used, but only in a minority of patients.
