acetylator

An acetylator is an individual whose rate of N-acetylation, a drug metabolism reaction, is determined by the activity of N-acetyltransferase enzymes, primarily NAT2. Acetylation converts certain drugs and carcinogens, especially aromatic amines and hydrazines, into acetylated metabolites that are usually more water-soluble and easier to eliminate.

The two main enzymes involved are NAT1 and NAT2. NAT2 polymorphisms cause variation in acetylation capacity and define distinct phenotypes commonly described as slow, intermediate, and rapid acetylators. The NAT2 gene contains multiple single-nucleotide polymorphisms; different haplotypes result in reduced or enhanced enzymatic activity. The acetylator phenotype is inherited, and its prevalence varies by ethnicity, with substantial slow acetylator proportions reported in some populations and higher rapid acetylator frequencies in others.

Substrates of NAT2 include the antituberculosis drug isoniazid, antihypertensives such as hydralazine, antiarrhythmics like procainamide, sulfonamides, and several other arylamine or hydrazine-containing compounds. Clinically, acetylator status influences drug exposure and toxicity. Slow acetylators often have higher plasma levels and greater risk of adverse effects, including isoniazid hepatotoxicity and hydralazine- or procainamide-induced drug reactions, whereas rapid acetylators may require higher or more frequent dosing to achieve therapeutic effect.

Testing for acetylator status can be done by NAT2 genotyping or phenotypic assays that measure acetylation capacity, though routine testing is not universal. In certain therapies, knowledge of acetylator status can inform dose adjustments and monitoring to balance efficacy and toxicity.