ABSTRACT
Methylsulfonyl-PCBs (MeSO2-PCBs) and some fungicides were studied for their functional effects on the glucocorticoid signal transduction in the Reuber rat hepatoma H-II-E-C3 cell line. 4-Substituted MeSO2-PCBs, tolylfluanid and ketoconazole displayed antagonistic effects on dexamethasone-induced tyrosine aminotransferase specific activity (IC50 ranging from 0.7-5.1 microM), but no agonist activity. These substances also had affinity to the mouse glucocorticoid receptor in competition binding studies, indicating that the inhibition of the middle cerebral artery occlusion-activity is indeed mediated by receptor binding. Thus, substances with a structural resemblance with a methyl sulfonyl group, such as the fungicide tolylfluanid, may inhibit glucocorticoid receptor-regulated gene transcription. In co-exposure experiments with three substances, multivariate modelling showed that the inhibitory effect of 4-MeSO2-2,5,6,2',4'-pentachlorobiphenyl (4-MeSO2-CB91), 4-MeSO2-2,3,6,2',4',5'-hexachlorobiphenyl (4-MeSO2-CB149) and tolylfluanid on tyrosine aminotransferase activity was close to additive. Thus, co-exposure to such different chemicals as persistent organic pollutants and pesticides may affect cells additively. Chemical interference with the glucocorticoid hormone system therefore deserves further attention in vivo.
Subject(s)
Aniline Compounds/pharmacology , Drug Synergism , Receptors, Glucocorticoid/drug effects , Sulfonamides/pharmacology , Tyrosine Transaminase/antagonists & inhibitors , Xenobiotics/pharmacology , Aniline Compounds/chemistry , Animals , Binding, Competitive/drug effects , Cell Line, Tumor , Data Interpretation, Statistical , Dexamethasone/pharmacology , Drug Stability , Ketoconazole/pharmacology , Mice , Polychlorinated Biphenyls/chemistry , Polychlorinated Biphenyls/pharmacology , Rats , Receptors, Glucocorticoid/antagonists & inhibitors , Sulfonamides/chemistry , Time Factors , Toluidines , Tritium , Tyrosine Transaminase/drug effects , Tyrosine Transaminase/pharmacologySubject(s)
Endotoxins/pharmacology , Energy Metabolism/drug effects , Animals , Carbon Radioisotopes , Cortisone/pharmacology , Cyproheptadine/pharmacology , Drug Antagonism , Endotoxins/administration & dosage , Enzyme Induction , Injections, Intraperitoneal , Injections, Intravenous , Kynurenine/biosynthesis , Lethal Dose 50 , Leucine/metabolism , Liver/metabolism , Mice , NAD/biosynthesis , NADP/biosynthesis , Orotic Acid/metabolism , Protein Biosynthesis , RNA/biosynthesis , Tryptophan/pharmacology , Tryptophan Oxygenase/pharmacology , Tyrosine Transaminase/pharmacologyABSTRACT
1. The administration of glucagon, cAMP [adenosine 3',5'-(cyclic)-monophosphate], BcAMP [6-N-2'-O-dibutyryladenosine 3',5'-(cyclic)-monophosphate] or adrenaline to foetal rats during the last 2 days of gestation evoked the appearance of tyrosine aminotransferase and enhanced the accumulation of glucose 6-phosphatase in the liver. In foetuses 1-2 days younger only BcAMP was effective. After birth liver glucose 6-phosphatase no longer responds to glucagon or BcAMP. Tyrosine aminotransferase is still inducible by these agents in 2-day-old rats, but not in 50-day-old rats. After adrenalectomy of adults glucagon or BcAMP can enhance the induction of the enzyme by hydrocortisone. The results indicate that the ability to synthesize tyrosine aminotransferase and glucose 6-phosphatase when exposed to cAMP develops sooner than the ability to respond to glucagon with an increase in the concentration of cAMP; the responsiveness of enzymes to different hormones changes with age. A scheme illustrating the sequential development of competence in regulating the level of an enzyme is presented. 2. Actinomycin inhibited the effects of glucagon and BcAMP on liver tyrosine aminotransferase and glucose 6-phosphatase in foetal rats. Growth hormone, insulin and hydrocortisone did not enhance the formation of these enzymes. 3. The time-course of accumulation of glucose 6-phosphatase in the kidney is different from that in the liver. Hormones that increase the accumulation in foetal liver do not do so in the kidney of the same foetus or in the livers of postnatal rats.
