N-acetylation of the heterocyclic amine batracylin by human liver.

Batracylin (8-aminoisoindolo[1,2-b]quinazolin-12(10 H)-one; BAT) is a heterocyclic amine that exhibits antitumor activity in a number of in vivo and in vitro models. The acetyl product has been implicated in BAT toxicity in animals, cells, and bacteria. The ability of human N-acetyltransferase (NAT) to form this product was investigated. Nine human liver samples were analyzed for NAT1 and NAT2 genotypes. Seven of the samples possessed at least one NAT14 allele. Three samples contained one or more NAT24 allele and were classified as rapid acetylators. The remaining six had two alleles associated with the slow phenotype. NAT activities were evaluated with BAT, sulfamethazine (SMZ), a preferential substrate for human NAT2, and p-aminobenzoic acid, a substrate for NAT1. BAT activities in the nine donor samples ranged from 14.9 to 0.56 nmol/min/mg. The mean apparent K(m) values in rapid acetylators for BAT, SMZ, and p-aminobenzoic acid were 6.59 +/- 3.21, 278 +/- 69.4, and 31.2 +/- 12.5 microM, respectively. The apparent K(m) values for slow acetylators did not differ from the rapid acetylator phenotype. However, a significant difference in the apparent V(max) for BAT and SMZ was observed between rapid and slow acetylators. Comparing the apparent intrinsic clearance (V(max)/K(m)) for BAT and SMZ, a significant correlation (r(2) = 0.97, p <.001) was observed. These data demonstrate that BAT N-acetylation is similar to SMZ, and suggests that BAT is a preferential substrate for human NAT2. Thus, rapid acetylators would be more likely to develop toxicity when exposed to this drug.