Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites: pH stability and synthesis by human and dog liver

doi:10.1016/0006-2952(96)00165-7

Biochemical Pharmacology

Volume 51, Issue 12, 28 June 1996, Pages 1679-1685

https://doi.org/10.1016/0006-2952(96)00165-7 Get rights and content

Abstract

Glucuronide conjugates of arylamines are thought to be important in the carcinogenic process. This study investigated the pH stability and synthesis of glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites by human and dog liver. Both dog and human liver slices incubated with 0.06 mM [³H]-4-aminobiphenyl produced the N-glucuronide of 4-aminobiphenyl as the major product. After 2 hr of incubation, the N-glucuronide of 4-aminobiphenyl represented 52 and 27% of the total radioactivity recovered by HPLC in dog and human, respectively. When 4-aminobiphenyl, N-hydroxy-4-aminobiphenyl, or N-hydroxy-N-acetyl-4-aminobiphenyl was added to human microsomes containing [¹⁴C]UDP-glucuronic acid, a new product peak was detected by HPLC. At 0.5 mM, the rate of glucuronidation was N-hydroxy-N-acetyl-4-aminobiphenyl > N-hydroxy-4-aminobiphenyl > 4-aminobiphenyl. The rate of formation of the N-glucuronide of 4-aminobiphenyl was similar to that observed with benzidine and N-acetylbenzidine. The glucuronides of 4-aminobiphenyl and N-hydroxy-4-aminobiphenyl were both acid labile with $T 12$ values of 10.5 and 32 min, respectively, at pH 5.5. The glucuronide of N-hydroxy-N-acetyl-4-aminobiphenyl was not acid labile with $T 12$ values at pH 5.5 and 7.4 of 55 and 68 min, respectively. The glucuronide of 4-aminobiphenyl was the most acid labile conjugate examined. Thus, the glucuronide of 4-aminobiphenyl is a major product of dog and human liver slice metabolism and likely to play an important role in the carcinogenic process.

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^☆: This work was supported by the Department of Veterans Affairs (T.V.Z. and B.B.D.).

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Research paperGlucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites: pH stability and synthesis by human and dog liver☆

Abstract

Biochem Biophys Res Commun

Biochim Biophys Acta

Biochem Pharmacol

Biochem Pharmacol

Tumors of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry

Br J Ind Med

The primary aromatic amines: Their biological properties and structure-activity relationships

Annu Rev Pharmacol Toxicol

Metabolism and pharmacokinetics of benzidine and its congeners in man and animals

Drug Metab Rev

Environmental exposure to N-aryl compounds

Chemical studies on tobacco smoke

J Anal Toxicol

Epidemiology of bladder cancer

Metabolic oxidation of the carcinogens 4-aminobiphenyl and 4,4′-methylene-bis(2-chloroaniline) by human hepatic microsomes and by purified rat hepatic cytochrome P-450 monooxygenases

Cancer Res

Human cytochrome P-450PA (P-450IA2), the phenacetin Odeethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines

Acetyl transferase-mediated metabolic activation of N-hydroxy-4-aminobiphenyl by human uroepithelial cells

Carcinogenesis

Metabolic activation and deactivation of arylamine carcinogens by recombinant human NAT1 and polymorphic NAT2 acetyltransferases

Carcinogenesis

Monomorphic and polymorphic human arylamine N-acetyltransferases: A comparison of liver isozymes and expressed products of two cloned genes

Mol Pharmocol

Molecular mechanism of slow acetylation of drugs and carcinogens in humans

Acetylation phenotype, carcinogen-hemoglobin adducts, and cigarette smoking

Cancer Res

Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens

Nature

Acetylator phenotype, aminobiphenyl-hemoglobin adduct levels, and bladder cancer risk in white, black, and Asian men in Los Angeles, California

J Natl Cancer Inst

N-Acetyltransferase phenotypes in the urinary bladder Carcinogenesis of a low risk population

Carcinogenesis

N-Acetyltransferase phenotype and risk in urinary bladder cancer: Approaches in molecular epidemiology. Preliminary results in Sweden and Denmark

Environ Health Perspect

Glucuronidation

Research paper
Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites: pH stability and synthesis by human and dog liver☆

Human cytochrome P-450_PA (P-450IA2), the phenacetin Odeethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines