Journal Article

The role of acetylation in the mutagenicity of the antitumor agent, batracylin

Gregory J. Stevens, Edmond J. LaVoie and Charlene A. McQueen

in Carcinogenesis

Volume 17, issue 1, pages 115-120
Published in print January 1996 | ISSN: 0143-3334
e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.1.115
The role of acetylation in the mutagenicity of the antitumor agent, batracylin

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The role of acetylation in the genotoxicity of the heterocyclic amine, batracylin, was evaluated in Salmonella typhimurium strains expressing various levels of N-and O-acetyltransferase activity. A significant correlation was observed between batracylin-induced mutagenicity and bacterial N-acetyltransferase activity. Strains with the greatest capacity for N-acetylating batracylin (YG 1012 and YG 1024) were the most sensitive to the mutagenic effects of the drug. The number of revertants/nmol batracylin and the formation of acetylbatracylin were ∼50-fold greater in YG 1024 compared to TA 98 which expresses endogenous levels of N-acetyltransferase. A similar response was observed with strains YG 1012 and TA 1538. Strains (TA 98/1, 8-DNP6 or TA 1538/1, 8-DNP6) which lack the ability to N-acetylate batracylin were the least sensitive to the mutagenic effects of the drug. At 1 μg/plate of batracylin, the number of revertants in TA 1538 and TA 98 was 4-fold higher than that observed in TA 1538/1, 8-DNP6 and TA 98/1, 8-DNP6. To determine if batracylin was a substrate for human N-acetyltransferases, assays were performed in bacteria expressing NAT1 or NAT2. Both strains were capable of N-acetylating batracylin. The strain expressing NAT2 (DJ 460) formed a significantly greater amount of acetylbatracylin, as well as batracylin-induced revertants, compared to the strain expressing NAT1 (DJ 400). These results demonstrate that the mutagenicity of batracylin is directly related to N-acetyltransferase activity. Data obtained in bacteria expressing either human NAT1 and NAT2 show that batracylin is capable of being bioactivated by both human enzymes. In addition, the higher enzyme activity and mutagenicity in bacteria expressing NAT2 suggests that batracylin is a substrate of this enzyme in humans.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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