Effects of dioxane on cytochrome P450 enzymes in liver, kidney, lung and nasal mucosa of rat

Abstract

The effect of acute and chronic dioxane administration on hepatic, renal, pulmonary and nasal mucosa P450 enzymes and liver toxicity were investigated in male rats. The acute treatment consisted of two doses (2 g/kg) of dioxane given for 2 days by gavage, whereas the chronic treatment consisted of 1.5% of dioxane in drinking water for 10 days. Both the acute and chronic dioxane treatments induced cytochrome P450 2B1/2- and P450 2E1-dependent microsomal monooxygenase activities (pentoxyresorufin O-depentylase and p-nitrophenol hydroxylase) in the liver, whereas in the kidney and nasal mucosa, only the 2E1 marker activities were enhanced. In addition in the liver, an induction of 2alpha-testosterone hydroxylase (associated with the constitutive and hormone-dependent P450 2C11) was also revealed, whereas the hepatic P450 4A-dependent omega-lauric acid hydroxylase was not enhanced by any dioxane treatment. These inductions were mostly confirmed by western blot analysis of liver, kidney and nasal mucosa microsomes. In the lung, no alteration of P450 activities was observed. To assess the mechanism of 2E1 induction, the hepatic, renal and nasal mucosa 2E1 mRNA levels were also examined. Following two kinds of dioxane administration, in the liver the 2E1 induction was not accompanied by a significant alteration of 2E1 mRNA levels, while both in the kidney and nasal mucosa the 2E1 mRNA increased about 2- to 3-fold, indicating an organ-specific regulation of this P450 isoform. Furthermore, dioxane was unable to alter the plasma alanine aminotransferase activity and hepatic glutathione (GSH) content, examined as an index of toxicity, when it was administered into rats with P450 2B1/2 and 2E1 preinduced by phenobarbital or fasting pretreatment. These results support the lack of or a poor formation of reactive and toxic intermediates during the biotrasformation of this solvent, even when its metabolism was enhanced by P450 inducers. The chronic administration of dioxane was also unable to induce the palmitoyl CoA oxidase, a marker of peroxisome proliferation, excluding this as a way to explain its toxicity. Thus, although the mechanism of dioxane carcinogenicity remains unclear, the present results suggest that the induction of 2E1 following a prolonged administration of dioxane might provide oxygen radical species, and thereby contribute to its organ-specific toxicity.

Species-specific induction of CYP2B by 2,4,6-tryphenyldioxane-1,3 (TPD)

“…CYP2B protein and mRNA are expressed, but not induced by PB, TPD and TCPOBOP in rat and mouse lungs. Several studies have shown the CYP2B-dependent metabolism of substrates in rodent kidneys and brains, although the CYP2B activity is significantly lower than in livers (Nannelli et al 2005;Parmar et al 1998). In our study, despite the presence of very Fig.…”

Modeling the Human Kinetic Adjustment Factor for Inhaled Volatile Organic Chemicals: Whole Population Approach versus Distinct Subpopulation Approach

“…Conversely, 1,4-dioxane was chosen as a poorly cleared chemical due to its low pulmonary clearance ( P b = 3650) and low hepatic extraction ratio. While benzene is a known substrate of CYP2E1 [18], for which extensive data on interindividual variability are available [19, 20], 1,4-dioxane was included in this study to facilitate the coverage of a range of physico/biochemical properties of potential substrates of CYP2E1 [21]. Chemical-specific parameters are indicated in Table 1 and were taken from the literature [10, 22, 23].…”

Distribution of 1,4-dioxane by combined inhalation plus oral exposure routes in rats

“…After the end of the inhalation exposure period, the concentration of DX in the tissues was governed primarily by two functions: (1) removal of DX from the blood by exhalation and metabolism in the liver [17,22,[31][32][33][34][35]; and (2) redistribution of DX from the storage tissues into the blood to re-establish equilibrium in the blood as DX was removed from the body.…”