metallothionein and 1-4-bis(2-(3-5-dichloropyridyloxy))benzene

We have investigated the effects of TCPOBOP (1,4-bis[2-(3,5- dichloropyridyloxy)]benzene), a potent cytochrome P-450-inducing agent [Poland, Mak, Glover, Boatman, Ebetino and Kende (1980) Mol. Pharmacol. 18, 571-580], on cytochrome P-450 isoenzyme expression in the mouse. Hepatic cytochrome P-450s from several distinct gene families were strikingly induced by a single dose of 75 micrograms of the compound. Northern-blot analysis demonstrated that this induction was almost certainly due to transcriptional activation of the cytochrome P-450 genes. The potency of this inductive effect was further reflected in the finding that cytochrome P-450 levels were still increased 12 weeks after a single injection of 75 micrograms of this compound. Interestingly, the mRNA levels of certain other genes, including those of metallothionein and the mouse major urinary proteins, were also induced. In view of the similarity in the effects of TCPOBOP and the synthetic glucocorticoid dexamethasone on mouse hepatic gene expression, we determined whether TCPOBOP acts through the glucocorticoid receptor. This did not, however, appear to be the case. Experiments with hypophysectomized animals demonstrated that TCPOBOP action was not regulated indirectly via the pituitary. In addition, induction of mouse Cyp2b protein by TCPOBOP in a primary culture of mouse hepatocytes suggests that the compound has a direct action on mouse liver. The above findings demonstrate that TCPOBOP is one of the most potent modulators of cytochrome P-450 gene expression described to date. It is not inconceivable that a single dose of this compound may alter hepatic gene expression for the majority of the lifespan of a mouse.

Topics: Animals; Cells, Cultured; Cytochrome P-450 Enzyme System; Dexamethasone; Enzyme Induction; Female; Gene Expression Regulation, Enzymologic; Liver; Male; Metallothionein; Mice; Mice, Inbred DBA; Microsomes, Liver; Oxazines; Phenobarbital; Protein Biosynthesis; Proteins; Pyridines; Recombinant Fusion Proteins; Repetitive Sequences, Nucleic Acid; RNA, Messenger; Transcription, Genetic; Transfection

The promoters of murine hepatocarcinogenesis phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) given to adult C3Hf female mice increased the content of total liver DNA by 1.6-1.8-fold each week after the beginning of treatment. Both compounds increased the aminopyrine-N-demethylase activity, decreased the glucose 6-phosphatase (G6Pase), alkaline phosphodiesterase I and alkaline phosphatase specific activities, but did not modify the gamma-glutamyltransferase levels. Both compounds decreased the abundance of tyrosine aminotransferase- and metallothionein I-related RNA transcripts. These findings confirmed the PB-like activity of TCPOBOP and showed that both chemicals had a pleiotropic effect on mouse liver, that was not limited to stimulation of drug metabolism, but also affected other hepatocyte functions.

Topics: Animals; Cell Differentiation; Female; gamma-Glutamyltransferase; Glucocorticoids; Glucose-6-Phosphatase; Liver; Metallothionein; Mice; Mice, Inbred C3H; Phenobarbital; Pyridines; RNA; Transcription, Genetic; Tyrosine Transaminase