Aldehydes are highly reactive aliphatic or aromatic molecules that are important in numerous physiological, pathogical and pharmacological processes. Various metabolic pathways are involved in the detoxification of aldehydes to less reactive forms: aldehyde dehydrogenases (ALDHs), alcohol dehydrogenases, aldo/keto reductases, glutathione-S- transferases. ALDHs oxidise aldehydes to the corresponding carboxylic acids using NAD or NADP as coenzymes. ALDHs have been discovered in practically all organisms: they exist in multiple isoforms and have a multiple subcellular localization. More than 160 ALDH cDNAs or genes have been isolated and sequenced from various sources, bacteria, yeast, fungi, plants and animals.

The eukaryotes ALDH genes can be divided into 18 families. The ALDH3 family includes enzymes able to oxidize medium chain aliphatic and aromatic aldehydes. The cytosolic form is highly expressed in the stomach, lung and cornea, but poorly if at all in normal liver. In rat liver cells, cytosolic ALDH3 is induced by polycyclic aromatic hydrocarbons (PAH) or chlorinated compounds, such as TCDD, and it increases during carcinogenesis. The increase in activity is in direct correlation with the degree of deviation, as has been seen in human and rat hepatoma cell lines, and in hepatoma induced in rats by administration of chemical carcinogens.

The increase of ALDH3 expression in hepatoma cells is one cause of their resistance against drug toxicity, such as oxazaphosphorines, and against aldehydes derived from lipid peroxidation. In fact, hepatoma cells with a high ALDH3 content are more resistant to the cytostatic and cytotoxic effect of lipid peroxidation aldehydes than those with a low content. Moreover, the increase in ALDH3 expression and activity has also been correlated with the growth of hepatoma cells. By inhibiting the enzyme with specific inhibitors or antisense oligonucleotides, hepatoma cells with a high ALDH3 content showed a decrease of growth, not accompanied by a decrease of cell viability, without the cells being exposed to any exogenous substance, drugs or pro-oxidants.

It remains open how ALDH3 influences cell growth. Probably its regulatory effect is mediated by some substrates metabolized by the enzyme and produced inside tumour cells, deriving from their normal metabolism. At this time, two ALDH substrates can be hypothesized: methional, and/or 4-hydroxynonenal.