ISSN:
1432-0738
Keywords:
Hemoglobin adducts
;
4,4′-Methylenebis(2-chloroaniline)
;
2-Chloro-4-[(3-chloro-4-nitrosophenyl)-methyl]benzenamine
;
4[(4-Amino-3-chlorophenyl)meth-yl]-2-chloro-N-hydroxybenzenamine
;
2-Amino-5-[(4-amino-3-chlorophenyl)methyl]-3-chloro-phenol
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract The capacity of N-oxidized metabolites of 4,4′-methylenebis(2-chloroaniline) (MBOCA) to form hemoglobin (Hb) adducts was determined in vitro, and the formation of Hb adducts following in vivo administration of MBOCA was assessed with or without prior induction of cytochrome P-450 enzymes with phenobarbital or β-naphthoflavone. Hb adduct formation was determined by electron-capture GLC of MBOCA as the heptafluorobutyryl derivative following mild acid hydrolysis of protein-bound MBOCA. The method was confirmed by gas chromatography-mass spectrometry with selected ion monitoring. N-hydroxy- and mononitroso-MBOCA, but not MBOCA itself, formed adducts to rat and human Hb in vitro in a dose-related manner. Binding was inhibited by cysteine and glutathione but not oxidized glutathione or methionine. Intravenous administration of as little as 0.04 μmol/kg N-hydroxy-MBOCA to rats resulted in measurable formation of MBOCA-Hb adducts (0.9 ng/50 mg Hb). Intraperitoneal administration of 0.5–50 mg/kg MBOCA to rats, and subcutaneous administration of 5–500 mg/kg MBOCA to rats and 4–100 mg/kg to guinea pigs resulted in dose-related formation of Hb adducts. MBOCA-Hb remained elevated in blood for greater than 10 weeks following a single subcutaneous dose in guinea pigs. Pretreatment of rats with phenobarbital induced microsomal benzphetamine N-demethylase (BND) activity and resulted in a small increase in in vitro N- andortho- hydroxylation of MBOCA, but did not increase in vivo Hb adducts. Pretreatment of rats with β-naphthoflavone induced microsomal aryl hydrocarbon hydroxylase as well as ethoxyresorufin-O-deethylase, and increased in vitro N- but notortho-hydroxylation of MBOCA. β-Naphthoflavone pretreatment increased the formation of MBOCA-Hb adducts when rats were dosed with MBOCA at 100 and 500 mg/kg, but not 20 mg/kg subcutaneously.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF02307306
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