-Acetyltransferase 2 Genotype-Dependent -Acetylation of Hydralazine in Human Hepatocytes.

Hydralazine is used in the treatment of essential hypertension and is under investigation for epigenetic therapy in the treatment of neoplastic and renal diseases. -acetyltransferase (NAT) 2 exhibits a common genetic polymorphism in human populations. After recombinant expression in yeast, human NAT2 exhibited an apparent Lineweaver-Burk constant () value (20.1 ± 8.8 M) for hydralazine over 20-fold lower than the apparent value (456 ± 57 M) for recombinant human NAT1 ( = 0.0016). The apparent value for recombinant human NAT1 (72.2 ± 17.9 nmol acetylated/min/mg protein) was significantly ( = 0.0245) lower than recombinant human NAT2 (153 ± 15 nmol acetylated/min/mg protein), reflecting 50-fold higher clearance for recombinant human NAT2. Hydralazine NAT activities exhibited a robust acetylator gene dose response in cryopreserved human hepatocytes both in vitro and in situ. Hydralazine NAT activities in vitro differed significantly with respect to NAT2 genotype at 1000 ( = 0.0319), 100 ( = 0.002), and 10 M hydralazine ( = 0.0029). Hydralazine NAT activities differed significantly ( < 0.001) among slow acetylator hepatocytes, (******). The in situ hydralazine -acetylation rates differed significantly with respect to NAT2 genotype after incubation with 10 ( = 0.002) or 100 M ( = 0.0015) hydralazine and were higher after incubation with 100 M (10-fold) than with 10 M (4.5-fold) hydralazine. Our results clearly document NAT2 genotype-dependent -acetylation of hydralazine in human hepatocytes, suggesting that hydralazine efficacy and safety could be improved by NAT2 genotype-dependent dosing strategies.