Arylamine N-acetyltransferase 2 (NAT2)

One of the earliest demonstrations of a pharmacogenetic problem affecting therapeutic agents was that of the N-acetyltransferase enzyme. This is an enzyme that N-acetylates arylamines carcinogens and heterocyclic amines. In 1960, it was reported that the metabolism of the anti-TB drug isoniazid was bimodality distributed in the population. Patients could be distiguished into slow and rapid acetylator phenotypes by exposing them to either isoniazid or some other arylamine and measuring their acetylator status (typically the ratio of acetyl-metabolite/parent compound in either plasma or urine). The enzyme was eventually called N-acetyltransferase 2 (NAT2).

The frequency of slow acetylators varied considerably across the world. Caucasian populations generally have about 50% frequency of slow acetylators, while East Asians such as Chinese and Japanese had about 20-30% slow acetylators.

For many years after the discovery of this genetic polymorphism, drug companies avoided developing drugs which were substrates of NAT2, until it became increasingly recognized in the 1980's that NAT2 wasn't the only genetic polymorphism affecting drug metabolism. With the discovery of genetic polymorphisms affecting pretty much all drug metabolism pathways, the strategy shifted to management of pharmacogenetic problems, rather than just avoiding it.