Covalent interaction of 3,3'-dichlorobenzidine with hepatic lipids. Enzymic basis and stability of the adducts.
Administration of a single oral dose (20 mg/kg) of [U-14C]3,3'-dichlorobenzidine to rats resulted in the in vivo covalent binding of the compound to hepatic lipids. More than 70% of the lipid-3,3'-dichlorobenzidine adducts were accounted for in microsomes. Loss of the lipid-bound 3,3'-dichlorobenzidine residues from either total liver or endoplasmic reticulum occurred in at least two phases--an initial fast phase and a terminal slow phase. In vitro studies with hepatic microsomes in the presence of antibodies to specific P450 isozymes and chemical inhibitors to determine the enzymes that activate 3,3'-dichlorobenzidine to the lipid-binding derivative(s) implicated cytochrome P450d. The 3,3'-dichlorobenzidine-bound microsomal lipids were not mutagenic to Salmonella TA98 in the Ames test. The results suggest that adduct formation between 3,3'-dichlorobenzidine and membrane lipids may provide a measure of 3,3'-dichlorobenzidine activation. It is speculated that covalent interaction of the compound with membrane lipids may modify cellular processes, leading to either enhancement or attenuation of carcinogenesis by the chemical.
Iba
M M
MM
Department of Pharmacology, Rutgers University-Busch Campus, Piscataway, NJ 08854-0789.
Lang
B
B
Thomas
P E
PE
Ghosal
A
A
D015101:3,3'-Dichlorobenzidine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001560:Benzidines / Q000378:metabolism*; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology* / Q000648:ultrastructure; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009152:Mutagenicity Tests; D009251:NADPH-Ferrihemoprotein Reductase / Q000276:immunology / Q000378:metabolism; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000906:Antibodies; D001560:Benzidines; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D015101:3,3'-Dichlorobenzidine; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D009251:NADPH-Ferrihemoprotein Reductase