Aldehyde dehydrogenase

Aldehyde dehydrogenase (ALDH) is a group of enzymes that play a crucial role in the metabolism of aldehydes in the body, converting them into carboxylic acids. This enzyme family is involved in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. ALDH enzymes are found in various tissues throughout the body, including the liver, where they are most abundant, as well as the stomach, kidneys, brain, and lungs.

Function

Aldehyde dehydrogenase catalyzes the chemical reaction in which an aldehyde, in the presence of NAD+ (nicotinamide adenine dinucleotide), is converted into a carboxylic acid. This reaction is vital for the detoxification of ethanol in the liver, where the enzyme alcohol dehydrogenase first oxidizes ethanol to acetaldehyde, a highly toxic compound. ALDH then oxidizes acetaldehyde to acetate, which is further metabolized to carbon dioxide and water, thus mitigating the toxic effects of alcohol consumption.

Isozymes

There are several isozymes of ALDH in humans, encoded by different genes. These isozymes vary in their kinetic properties, tissue distribution, and substrate specificity. The most well-known isozymes include ALDH1A1, found in the cytosol, and ALDH2, located in the mitochondria. ALDH2 is particularly significant in the metabolism of alcohol; a genetic polymorphism that results in a less active form of ALDH2 is common in East Asian populations, leading to the accumulation of acetaldehyde upon alcohol consumption and the associated flushing response.

Clinical Significance

The activity of ALDH enzymes has significant implications for various medical conditions and drug interactions. Inadequate ALDH function can lead to the accumulation of toxic aldehydes in the body, contributing to the pathogenesis of diseases such as alcoholic liver disease, Alzheimer's disease, and certain types of cancer. Furthermore, individuals with the ALDH2 polymorphism are at a higher risk of developing esophageal cancer due to the toxic effects of acetaldehyde.

In addition to its role in disease, ALDH activity is also a critical factor in the pharmacokinetics of certain drugs. For example, the anticancer drug cyclophosphamide is activated by ALDH enzymes. Inhibitors of ALDH, such as disulfiram, are used in the treatment of alcohol dependence by blocking the oxidation of acetaldehyde and producing unpleasant symptoms upon alcohol intake.

Genetic Variations

Genetic variations in the genes encoding ALDH isozymes can significantly affect their function. These variations can lead to differences in the metabolism of aldehydes among individuals, influencing their susceptibility to aldehyde-related diseases and their response to certain medications. The study of these genetic variations is an important area of research in pharmacogenomics and personalized medicine.

See Also

• Alcohol dehydrogenase
• Acetaldehyde
• Carboxylic acid
• Pharmacogenomics
• Disulfiram