Mouse Liver Effects of Cyproconazole, a Triazole Fungicide: Role of the Constitutive Androstane Receptor

Abstract

Cyproconazole, a triazole fungicide, causes hepatocellular adenomas and carcinomas in CD-1 mice at dose levels of 100 and 200 ppm. The constitutive androstane receptor (CAR) has been shown to play a significant role in the overall mode of action for several nongenotoxic rodent carcinogens such as phenobarbital. The liver effects of dietary cyproconazole or phenobarbital were investigated after 2, 7, or 14 days in male CD-1, C57BL/6J, and C3H/HeNClrBR mice. Cyproconazole produced similar, dose-responsive effects in all three strains of mice, and the response was similar to that of phenobarbital. Subsequently, Car-null and wild-type male mice on a C3H/HeNClrBR background were administered 200 or 450 ppm cyproconazole, or 850 ppm phenobarbital for up to 7 days. In wild-type mice, 200 ppm cyproconazole caused liver hypertrophy, increased liver weight and cell proliferation, single-cell necrosis and fat vacuolation, effects generally similar to those caused by 850 ppm phenobarbital. Plasma cholesterol was decreased by both compounds, but cyproconazole had a greater effect. The higher dose (450 ppm) of cyproconazole caused similar changes, but greater evidence of liver damage was observed, including a large increase in plasma transaminases. Induction of CAR target genes Cyp2b10 and Gadd45beta was observed with both compounds, whereas the cell cycle regulatory gene Mdm2 was unaffected. In Car-null mice, the effects noted with either cyproconazole or phenobarbital were absent or greatly diminished. These experiments demonstrate that short-term liver effects of cyproconazole in mice are CAR-dependent and similar to those of phenobarbital, a known nongenotoxic rodent liver carcinogen.

Effect of Breed upon Cytochromes P450 and Phase II Enzyme Expression in Cattle Liver

“…The immunoblotting, where we used the same anti-rat CYP2B1/2 polyclonal antibody reported by Nebbia et al (2003) and Sivapathasundaram et al (2001), gave significant results that agreed with CYP2B6-like expression profile, but not with catalytic activities. A good correlation was obtained between 16␤-OHT and CYP2B6-like gene expression (especially in BA), thereby confirming data reported in the mouse by Peffer et al (2007).…”

“…In cattle, this isoform was believed to be poorly involved in TST hydroxylation (Sivapathasundaram et al, 2001;Ioannides, 2006), but recently, veal calf liver microsomes were proved able to produce, out of 6␤-and 2␤-OH TST, detectable amounts of 16␤-OH TST, too (Capolongo et al, 2003); besides, a 3-fold increase in 16␤-OH TST production was noticed in liver microsomes from beef cattle induced with phenobarbital (Cantiello et al, 2006), which up-regulates CYP2B10 expression in the mouse (Peffer et al, 2007). In our study, CYP2B-dependent DMEs activities were clearly and significantly higher in CH.…”

Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

“…Actually, thiazolidinediones (TZDs) could favor lipid accretion and worsen liver function more easily in the context of pre-existent induction of PPARc expression [179,180], as discussed in the next section; (3) Glucocorticoid receptor (GR) whose activation plays a central role in glucocorticoid-induced hepatic lipogenesis and steatosis [165,181]. Finally, some investigations suggest that the activation of the constitutive androstane receptor (CAR) could play a role in phenobarbital-induced hepatic steatosis [182]. However, steatosis is rarely observed in patients treated with phenobarbital [1], and liver fat accumulation in mice is only transient and disappears after 1 week of treatment with this CAR activator [182].…”

“…Finally, some investigations suggest that the activation of the constitutive androstane receptor (CAR) could play a role in phenobarbital-induced hepatic steatosis [182]. However, steatosis is rarely observed in patients treated with phenobarbital [1], and liver fat accumulation in mice is only transient and disappears after 1 week of treatment with this CAR activator [182]. In addition, CAR activation with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) reduces hepatic lipogenesis and prevents fatty liver induced by obesity or a methionine cholinedeficient diet [183][184][185].…”

Meeting The Common Needs of a More Effective and Efficient Testing and Assessment Paradigm for Chemical Risk Management

“…An example using conazoles illustrates how new methods such as microarray analyses have informed MOA. Using an integrated approach involving histopathological and clinical chemistry results with gene expression profiles, a nongenotoxic mechanism of rodent hepatocarcinogenesis involving activation of the constitutive androstane receptor (CAR), hepatocyte hypertrophy, induction of CYP2B, induction of cell proliferation, and inhibition of apoptosis was found for specific conazoles (Chen et al, 2009;Peffer et al, 2007). Such MOA analyses will be valuable in revealing early biomarkers of disease using HTP methods.…”