Abstract
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 < .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.
Footnotes
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Send reprint requests to: Dr. Charlene A. McQueen, Department of Pharmacology and Toxicology, University of Arizona, P.O. Box 210207, Tucson, AZ 85721. E-mail: Mcqueen{at}pharmacy.arizona.edu
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↵1 Present address: Agouron Pharmaceuticals Research Laboratories, San Diego, CA.
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Human liver samples were generously provided by Brent Bardsley, Human Cell Culture Center, Folkston, Georgia. G.J.S. was supported by National Institutes of Health Training Grant ES07091 and a Procter and Gamble predoctoral fellowship. Studies were supported by Grant ES-05174 (C.A.M.), Center Grant P30 ES06694 and the Wellcome Trust (E.S. and M.P.). Presented in part at the 35th Annual Meeting of the Society of Toxicology, Anaheim, California, March 1996.
- Abbreviations used are::
- BAT
- batracylin
- PABA
- p-aminobenzoic acid
- SMZ
- sulfamethazine
- NAT
- N-acetyltransferase
- ABAT
- N-acetylbatracylin
- 2-AF
- 2-aminofluorene
- Received December 31, 1998.
- Accepted May 24, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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