Binding of N-acetylbenzidine and N,N'-diacetylbenzidine to hepatic DNA of rat and hamster in vivo and in vitro
Benzidine, a potent hepatocarcinogen in rodents, is readily metabolised to acetylated derivatives. In this study, the covalent binding of (/sup 3/H-acetyl)N-acetylbenzidine and (/sup 3/H-acetyl)N,N'-diacetylbenzidine to liver DNA in rats and hamsters was investigated. Binding to liver DNA of rats at 1 or 7 days after i.p. injection of N-acetylbenzidine was 2-fold higher than that observed in the liver DNA of hamsters which had been similarly treated. Analysis of enzymically hydrolysed DNA from both species indicated the presence of a single adduct which co-eluted with N-(deoxyguanosin-8-yl)-N'-acetylbenzidine. In vitro treatment of rat or hamster liver slices with N-acetylbenzidine also resulted in covalent binding to hepatic DNA and the identical DNA adduct was detected at levels comparable to that observed in vivo. When N,N'-diacetylbenzidine was injected i.p. into rats, a comparatively low level of binding to liver DNA was observed. Following enzymic hydrolysis, the major DNA adduct detected by h.p.l.c. analysis was again N-(deoxyguanosin-8-yl)-N'-acetylbenzidine accompanied by a small amount of N-(deoxyguanosin-8-yl)-N,N'-diacetylbenzidine. In vitro incubation of N,N'-diacetylbenzidine with rat liver slices resulted in DNA binding levels similar to that observed with N-acetylbenzidine. In contrast to what was found in vivo, N-(deoxyguanosin-8-yl)-N,N'-diacetylbenzidine was the major adduct detected in DNA from rat liver slices. These data suggest that both N-hydroxy-N'-acetylbenzidine and N-hydroxy-N,N'-diacetylbenzidine are proximate carcinogenic species of benzidine, with N-hydroxy-N'-acetylbenzidine the more important. The low level of N-(deoxyguanosin-8-yl)N,N'-diacetylbenzidine observed in vivo may be due to its rapid repair. Alternatively, N-sulphonyloxy-N,N'-diacetylbenzidine, which would produce this adduct on reaction with DNA, may be efficiently detoxified in vivo.
- Research Organization:
- Cancer Research Unit, University of York, UK
- OSTI ID:
- 7003193
- Journal Information:
- Carcinogenesis (N.Y.); (United States), Journal Name: Carcinogenesis (N.Y.); (United States) Vol. 5:3; ISSN CRNGD
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
560305* -- Chemicals Metabolism & Toxicology-- Vertebrates-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADDUCTS
AMINES
ANIMALS
AROMATICS
BENZIDINE
BODY
CHEMICAL BONDS
DIGESTIVE SYSTEM
DNA
DNA ADDUCTS
GLANDS
HAMSTERS
IN VITRO
IN VIVO
LIVER
MAMMALS
METABOLISM
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANS
RATS
RODENTS
VERTEBRATES