TY - JOUR T1 - <em>N</em>-Acetylation of the Heterocyclic Amine Batracylin by Human Liver JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 966 LP - 971 VL - 27 IS - 9 AU - Gregory J. Stevens AU - Mark Payton AU - Edith Sim AU - Charlene A. McQueen Y1 - 1999/09/01 UR - http://dmd.aspetjournals.org/content/27/9/966.abstract N2 - Batracylin (8-aminoisoindolo[1,2-b]quinazolin-12(10H)-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 humanN-acetyltransferase (NAT) to form this product was investigated. Nine human liver samples were analyzed forNAT1 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, andp-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 Km 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 Km values for slow acetylators did not differ from the rapid acetylator phenotype. However, a significant difference in the apparentVmax for BAT and SMZ was observed between rapid and slow acetylators. Comparing the apparent intrinsic clearance (Vmax/Km) for BAT and SMZ, a significant correlation (r2 = 0.97,p &lt; .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. The American Society for Pharmacology and Experimental Therapeutics ER -