| Autor: |
Chen TH; Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824., Kuslikis BI, Braselton WE Jr |
| Jazyk: |
angličtina |
| Zdroj: |
Archives of toxicology [Arch Toxicol] 1991; Vol. 65 (3), pp. 177-85. |
| DOI: |
10.1007/BF02307306 |
| Abstrakt: |
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 beta-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 mumol/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- and ortho-hydroxylation of MBOCA, but did not increase in vivo Hb adducts.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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