Molecular mechanisms of cold-induced CYP1A activation in rat liver microsomes

Abstract

Cytochrome P4501A (the CYP1A1 and CYP1A2 enzymes) is known to metabolize anthropogenic xenobiotics to carcinogenic and mutagenic compounds. CYP1A1 transcriptional activation is regulated via the aryl hydrocarbon receptor (AhR)-dependent signal transduction pathway. CYP1A2 activation may occur through the AhR-dependent or AhR-independent signal transduction pathways. We used male Wistar rats to explore possible mechanisms of CYP1A activation induced by exposure to cold and the effects of the protein-tyrosine kinase inhibitors genistein, herbimycin A, and geldanamycin on the properties of hepatic CYP1A1 and CYP1A2 proteins following exposure to cold and to classic CYP1A inducers. The molecular mechanisms of cold-induced CYP1A1 and CYP1A2 activation are different. The CYP1A2 activation apparently occurs at the post-transcriptional level. The CYP1A1 activation, whether caused by exposure to cold or by classic CYP1A inducers, is AhR-dependent and occurs at the transcriptional level. Protein tyrosine kinase inhibitors have no effect on benzo(a)pyrene-induced CYP1A expression but alter cold-induced CYP1A1 activity and the CYP1A1 mRNA level. Thus, treatment with herbimycin A or geldanamycin leads to an increase in CYP1A1 activity, while treatment with genistein increases CYP1A1 mRNA expression and decreases CYP1A2 activity. These data elucidate the molecular mechanisms of cold-induced CYP1A activation and the role of protein kinases in the regulation of CYP1A during exposure to cold. Our results can also help identify the differences between the molecular mechanisms underlying the effects of the classic CYP1A inducers and the effects of cooling.

Comparison of the Effects of Cold on Cytochromes Р450 1А in the Rat Lungs Versus Liver

“…1. Previously we demonstrated that cold is a weak inducer of CYP1A in rat liver when rats were exposed to 4ºС for 5 or 10 days [9]. In the present study, we exposed rats to 4ºС for 1, 5 or 10 days.…”

“…The increase of activity and CYP1A apoprotein content in the liver of rats on days 5 and 10 of cooling are discussed at length in our previous report [9]. In that work we made some conclusions regarding the mechanisms of CYP1A induction in the rat liver as a result of exposure to cold: CYP1A1 is induced transcriptionally via the AhR-dependent signal transduction pathway, whereas the activation of CYP1A2 by cooling is a posttranscriptional phenomenon.…”

“…We reported previously [9] that CYP1A1 and CYP1A2 in rat liver are induced by exposure to cold via the Ah-receptor-dependent signaling pathway. Apparently, this process involves some endogenous intermediary or intermediaries, which must either be AhR ligands or participate in metabolic pathways that synthesize a compound that is an AhR ligand.…”

“…For a long time it has been thought that CYP1A substrates consist exclusively of anthropogenic xenobiotics such as PAH, but recent data suggest that this is not the case. CYP1A inducers are not only PAH-like xenobiotics, but also compounds from other classes of chemicals, including endogenous compounds, nutrients (vitamins, tryptophan) [4], hyperoxia [5], and mechanical factors, such as ultrasound [6], hydrodynamic shear [7], ultraviolet light [8], and cold [9].…”

Integrative analysis of transcriptomic and metabolomic profiling of ascites syndrome in broiler chickens induced by low temperature

“…41 Experiments on rats showed that long-term exposure to low temperature changed activities of cytochromes CYP1A1 and CYP1A2 in the liver. 42 Low temperature induced-AS chicken were under hypoxia. Couroucli (2002) discovered that hyperoxia (95% oxygenation) increases activity, mRNA and the protein level of CYP1A1 in the lungs and liver of Sprague-Dawley rats, while inversely hypoxia could restrict them.…”