Vol. 27, Issue 9, 966-971, September 1999

N-Acetylation of the Heterocyclic Amine Batracylin by Human Liver

Gregory J. Stevens,¹ Mark Payton, Edith Sim, and Charlene A. McQueen

Department of Pharmacology and Toxicology (G.J.S., C.A.M.), University of Arizona, Tucson, Arizona; and Department of Pharmacology (M.P., E.S.), University of Oxford, Oxford, United Kingdom

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 NAT1*4 allele. Three samples contained one or more NAT2*4 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 µM, 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 (r² = 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.