The role of n-acetylation in the genotoxicity of the antitumor agent, batracylin.

Persistent Link:
http://hdl.handle.net/10150/187284
Title:
The role of n-acetylation in the genotoxicity of the antitumor agent, batracylin.
Author:
Stevens, Gregory John.
Issue Date:
1995
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Batracylin (8-aminoisoindolo (1,2-b) quinazolin-12(10H)-one), a heterocyclic amine developed as an antitumor agent, displays species variation in its adverse effects. Studies were initiated to determine if N-acetyltransferase plays a role in the observed species difference using genotoxicity as a toxicological endpoint. Initial studies examining batracylin genotoxicity demonstrated that the drug was mutagenic in Salmonella typhimurium, and addition of an S9 activating system was required for its mutagenicity. The N-acetylated metabolite of batracylin, acetylbatracylin, was mutagenic in the presence and absence of S9. Mutagenicity assays performed in bacteria expressing various levels of N-acetyltransferase established a correlation between batracylin mutagenicity and N-acetyltranferase activity. Batracylin was also found to be genotoxic in rat (F-344) and mouse (C-57B1/6J and A/J) hepatocytes. The genotoxic effects of batracylin were greater in rat cells than in mouse cells. It was determined that the species variations were due to differences in N-acetylation. Acetylation of batracylin in rat hepatic cytosol was six-fold greater than mouse cytosol. No significant difference was observed between the two mouse strains. Studies were also conducted to determine if batracylin was a substrate for human N-acetyltransferase. Studies showed that human hepatic N-acetyltransferases enhanced the mutagenic effects of batracylin. Human liver samples phenotyped by measuring sulfamethazine acetylation showed a significant difference in the rate of batracylin acetylation between rapid and slow acetylators. The activity in rapid acetylators was similar to that observed in rat liver and activity measured in slow acetylators was similar to mouse liver. Kinetic parameters for batracylin acetylation were compared to those for sulfamethazine and para-aminobenzoic acid. The mean Km for all three substrates did not differ among phenotypes; however, differences were observed in the Vmax for batracylin and sulfamethazine, but not for para-aminobenzoic acid. A significant correlation was observed between batracylin and sulfamethazine intrinsic clearance (Vmax/Km), suggesting batracylin is acetylated by the N-acetyltransferase 2. Since a high rate of batracylin acetylation has been associated with adverse effects, patients who are rapid acetylators would be at risk of developing drug-induced toxicity when exposed to batracylin.
Type:
text; Dissertation-Reproduction (electronic)
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology and Toxicology; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
McQueen, Charlene A.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleThe role of n-acetylation in the genotoxicity of the antitumor agent, batracylin.en_US
dc.creatorStevens, Gregory John.en_US
dc.contributor.authorStevens, Gregory John.en_US
dc.date.issued1995en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractBatracylin (8-aminoisoindolo (1,2-b) quinazolin-12(10H)-one), a heterocyclic amine developed as an antitumor agent, displays species variation in its adverse effects. Studies were initiated to determine if N-acetyltransferase plays a role in the observed species difference using genotoxicity as a toxicological endpoint. Initial studies examining batracylin genotoxicity demonstrated that the drug was mutagenic in Salmonella typhimurium, and addition of an S9 activating system was required for its mutagenicity. The N-acetylated metabolite of batracylin, acetylbatracylin, was mutagenic in the presence and absence of S9. Mutagenicity assays performed in bacteria expressing various levels of N-acetyltransferase established a correlation between batracylin mutagenicity and N-acetyltranferase activity. Batracylin was also found to be genotoxic in rat (F-344) and mouse (C-57B1/6J and A/J) hepatocytes. The genotoxic effects of batracylin were greater in rat cells than in mouse cells. It was determined that the species variations were due to differences in N-acetylation. Acetylation of batracylin in rat hepatic cytosol was six-fold greater than mouse cytosol. No significant difference was observed between the two mouse strains. Studies were also conducted to determine if batracylin was a substrate for human N-acetyltransferase. Studies showed that human hepatic N-acetyltransferases enhanced the mutagenic effects of batracylin. Human liver samples phenotyped by measuring sulfamethazine acetylation showed a significant difference in the rate of batracylin acetylation between rapid and slow acetylators. The activity in rapid acetylators was similar to that observed in rat liver and activity measured in slow acetylators was similar to mouse liver. Kinetic parameters for batracylin acetylation were compared to those for sulfamethazine and para-aminobenzoic acid. The mean Km for all three substrates did not differ among phenotypes; however, differences were observed in the Vmax for batracylin and sulfamethazine, but not for para-aminobenzoic acid. A significant correlation was observed between batracylin and sulfamethazine intrinsic clearance (Vmax/Km), suggesting batracylin is acetylated by the N-acetyltransferase 2. Since a high rate of batracylin acetylation has been associated with adverse effects, patients who are rapid acetylators would be at risk of developing drug-induced toxicity when exposed to batracylin.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairMcQueen, Charlene A.en_US
dc.contributor.committeememberDorr, Robert T.en_US
dc.contributor.committeememberLiebler, Daniel C.en_US
dc.contributor.committeememberSipes, I. Glennen_US
dc.identifier.proquest9604510en_US
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