Subject(s)
Carcinogens/toxicity , Methylenebis(chloroaniline)/toxicity , Animals , Carcinogenicity Tests , Carcinogens/chemical synthesis , Carcinogens/chemistry , Carcinogens/pharmacology , Female , Government Regulation , Guidelines as Topic , Humans , Male , Methylenebis(chloroaniline)/chemical synthesis , Methylenebis(chloroaniline)/chemistry , Methylenebis(chloroaniline)/pharmacology , Mice , Models, Biological , Occupational Exposure/adverse effects , Occupational Exposure/legislation & jurisprudence , Rats , United StatesABSTRACT
1. The effect of 4,4'-methylene bis(2-chloroaniline) (MOCA), 4,4'-methylene dianiline (MDA) and 4,4'-sulphonyldianiline (Dapsone) in vivo on xenobiotic biotransformation in male rat liver was studied. 2. Treatment with MOCA or MDA but not Dapsone caused a dose-dependent increase in ethoxyresorufin O-deethylase activity and a concomitant decrease in aldrin epoxidase activity in male rats. 3. Treatment with MOCA or MDA resulted in dose-dependent increases in ethoxycoumarin O-deethylation and epoxide hydrolation, while only MOCA induced cytosolic glutathione S-transferase activity. 4. Treatment with Dapsone resulted in no changes in xenobiotic biotransformation except for the induction of aniline hydroxylation. 5. The results are consistent with the contention that there is a relationship between carcinogenic chemicals and particular alterations in the activities of biotransformation enzymes.
Subject(s)
Aniline Compounds/pharmacology , Benzhydryl Compounds/pharmacology , Biotransformation , Dapsone/pharmacology , Methylenebis(chloroaniline)/pharmacology , Microsomes, Liver/enzymology , 7-Alkoxycoumarin O-Dealkylase/metabolism , Aniline Hydroxylase/metabolism , Animals , Cytochrome P-450 CYP1A1 , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , Glutathione Transferase/metabolism , Male , Microsomes, Liver/drug effects , Mixed Function Oxygenases/metabolism , Mutagens , Oxidoreductases/metabolism , Rats , Rats, Inbred StrainsABSTRACT
The mutagenic properties of Ethacure 300, Cyanacure and Polacure 740M, all possible substitutes for the industrial carcinogen, 4,4'-methylene bis(2-chloroaniline), have been determined in Salmonella typhimurium strains TA100, TA98, TA1535 and TA1537. These data have been compared with the effects of these chemicals on ethoxyresorufin O-deethylase (EROD) activity and aldrin epoxidase (AE) activity in rat liver. Ethacure 300 was clearly positive in both TA100 and TA98 bacterial strains, while Cyanacure was positive only in TA100. Polacure 740M was negative in all strains. Ethacure 300 caused a 28-fold induction of EROD while Cyanacure caused a doubling. Polacure 740M was without effect. Neither Ethacure 300 nor Cyanacure affected AE, while Polacure 740M caused an increase at only the lower dose tested. Thus there was excellent correlation between mutagenicity and EROD induction. A similar correlation was noted for six other structurally related compounds giving support to the contention that the ability of a chemical to induce EROD bears some relationship to its carcinogenic potential.
Subject(s)
Aniline Compounds/pharmacology , Benzhydryl Compounds/pharmacology , Methylenebis(chloroaniline)/pharmacology , Microsomes, Liver/enzymology , Mutagens , Phenylenediamines/pharmacology , Propylene Glycols/pharmacology , para-Aminobenzoates , 4-Aminobenzoic Acid/pharmacology , Animals , Biotransformation/drug effects , Cytochrome P-450 CYP1A1 , Cytochrome P-450 Enzyme System/metabolism , In Vitro Techniques , Mixed Function Oxygenases/metabolism , Mutagenicity Tests , Oxidoreductases/metabolism , Rats , Rats, Inbred Strains , Salmonella typhimurium/drug effects , Structure-Activity RelationshipABSTRACT
Primary cultures of hepatocytes isolated by collangenase perfusion of adult rats were used as an in vitro system for assessing cytotoxicity of xenobiotics. The leakage of two intracellular enzymes, lactate dehydrogenase (LDH) and glutamic oxaloacetic transaminase (GOT) were compared as indicators of cell damage. Although some differences in sensitivity were detected, either enzyme could be used to evaluate the cytotoxic potential of a chemical. Release of LDH was also compared with determination of cell viability by trypan blue uptake. For cultures exposed to 2-aminofluorene or alpha-naphthylisothiocyanate both endpoints gave comparable results. The cytotoxicities of benzo(a)pyrene, 2-aminofluorene, 3,2'-dimethyl-4-aminobiphenyl, methylene-bis-2-chloroaniline, aflatoxin B1, pyrene, aflatoxin G2, fluorene, methapyrilene, and alpha-naphthylisothiocyanate were monitored by the release of LDH and were found to be related to the length of exposure and concentration of the chemical. For chemicals that elicited DNA repair, little or no cytoxicity was observed at genotoxic concentrations in the hepatocyte primary culture/DNA repair test. Thus, measurement of enzyme release provides a means of quantifying cytotoxicity. Moreover, the use of hepatocyte primary cultures permits identification of genotoxic effects versus general cytotoxic effects of chemicals.
