Dose–response involvement of constitutive androstane receptor in mouse liver hypertrophy induced by triazole fungicides

Tamura, Kazutoshi; Inoue, Kaoru; Takahashi, Miwa; Matsuo, Saori; Irie, Kaoru; Kodama, Yukio; Ozawa, Shogo; Nishikawa, Akiyoshi; Yoshida, Midori

doi:10.1016/j.toxlet.2013.05.011

Cited by 26 publications

(33 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased cell proliferation is one of key events in hepatocarcinogenesis, and PB is known to increase hepatocellular proliferation at an early phase (Elcombe et al, 2014;Tamura et al, 2013). However, in the present study, IMA did not increase hepatocellular proliferation when used at doses that would induce liver hypertrophy or hepatotoxicity.…”

Section: Discussioncontrasting

confidence: 78%

“…However, there was no difference of the intensity of liver hypertrophy between WT and CARKO mice, indicating that contribution of CAR to the liver hypertrophy was little or none. Liver hypertrophy induced by PB is known to be mediated by CAR (Tamura et al, 2013). The present study indicated the pathway for liver hypertrophy was different from that of IMA-induced tumorigenesis, and that the mechanisms of liver hypertrophy of IMA was different from those of PB.…”

Section: Discussionmentioning

confidence: 51%

“…2 or with monoclonal mouse anti-proliferating cell nuclear antigen (PCNA) antibodies (Clone PC10; DAKO, Glostrup, Denmark) in Exps. 1 and 2, the sections were reacted with secondary antibodies conjugated to peroxidase-labeled dextran polymers (Histofine Simple Stain mouse MAX PO; Nichirei, Tokyo, Japan) and visualized by 3-3′-diaminobenzidine reaction (Sigma Chemical Co., St. Louis, MO, USA) in the same manner as in our previous study (Tamura et al, 2013.…”

Section: Pathological and Immunohistochemical Examination Of The Livermentioning

confidence: 99%

“…2), 4, and 13 (Exp. 1), hepatocyte proliferation was evaluated by grading of PCNA-positive hepatocytes (Tamura et al, 2013). Briefly, five fields of view from the whole median lobe were randomly selected from each animal.…”

Section: Analysis Of Proliferation In the Livermentioning

confidence: 99%

“…Various chemicals activate multiple nuclear receptors and increase the expression of CYPs in the mouse liver. Because CYP expression can be altered following treatment with various doses of different chemicals, it is difficult to identify which nuclear receptors are involved in liver hypertrophy in single-dose studies (Tamura et al, 2013;Sakamoto et al, 2015). Therefore, multiple-dose studies using CARKO mice are needed to investigate the relationship between liver changes, including hypertrophy, and the involvement of nuclear receptors.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

A crucial role of constitutive androstane receptor (CAR) in liver tumor development by imazalil in mice

et al. 2016

Self Cite

View full text Add to dashboard Cite

-To clarify the major pathway of liver tumor development induced by imazalil (IMA), an imidazole fungicide, male constitutive androstane receptor (CAR)-knockout (CARKO) and wild-type (WT) mice were treated with IMA at 500 ppm in the diet up to 27 weeks after initiation by diethylnitrosamine. After 27 weeks of treatment, neither altered foci nor adenomas were significantly increased in CARKO mice, whereas both eosinophilic altered foci and adenomas were increased in WT mice. After 4 or 13 weeks of IMA treatment, liver hypertrophy was observed at the tumor-inducible dose without differences among genotypes or durations. Analysis of hepatic drug metabolite enzymes, performed after administration of multiple doses during a 1-week period, indicated that pregnane X receptor might be involved in liver hypertrophy because IMA markedly elevated Cyp3a11 and Cyp2b10 expression levels in a dose-dependent manner in both genotypes. Our results demonstrated that the CAR pathway was the main mechanism of liver tumor development induced by IMA. The carcinogenic pathway was different from that of liver hypertrophy.

show abstract

Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 51%

Section: Pathological and Immunohistochemical Examination Of The Livermentioning

confidence: 99%

Section: Analysis Of Proliferation In the Livermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A crucial role of constitutive androstane receptor (CAR) in liver tumor development by imazalil in mice

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

Effects of tebuconazole on cytochrome P450 enzymes, oxidative stress, and endocrine disruption in male rats

Yang

Liu

Liao

et al. 2018

Environmental Toxicology

View full text Add to dashboard Cite

The major objective of the present study was to determine the ability of a triazole fungicide tebuconazole to induce cytochrome P450-dependent monooxygenases, oxidative stress, and endocrine-disrupting activity using male rats treated with tebuconazole at 10, 25, and 50 mg/kg p.o. once daily for 28 days. In liver, tebuconazole dose-dependently increased microsomal contents of cytochrome P450 and cytochrome b and the activities of NADPH-cytochrome P450 reductase, 7-ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, pentoxyresorufin O-dealkylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase. In kidney, tebuconazole increased 7-ethoxycoumarin O-deethylase activity without affecting other monooxygenase activities. In marked contrast to liver and kidney, tebuconazole decreased testicular 7-ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase activities. The results of immunoblot analysis of liver microsomes of controls and tebuconazole-treated rats revealed that tebuconazole induced CYP1A1/2, CYP2B1/2, CYP2E1, and CYP3A proteins in liver. Additions of tebuconazole to liver microsomes inhibited microsomal 7-ethoxycoumarin O-deethylase activity in vitro (IC = 1.50-1.69 µM). Treatment of rats with tebuconazole decreased glutathione content and increased glutathione S-transferase, superoxide dismutase, catalase, and glutathione peroxidase activities in liver; increased superoxide dismutase activities in kidney and testis; but decreased glutathione S-transferase activity in testis. Treatments with tebuconazole decreased serum testosterone concentration and cauda epididymal sperm count. The present study demonstrates that tebuconazole induces a multiplicity of CYPs and oxidative stress in liver; inhibits testicular P450 and glutathione S-transferase activities; and produces anti-androgenic effects in male rats.

show abstract

Hepatotoxic effects of (tri)azole fungicides in a broad dose range

et al. 2014

View full text Add to dashboard Cite

The toxicological relevance of effects observed at molecular stage, which occur at dose levels well below classical no-observed adverse effect levels is currently subject to controversial scientific debate. While the importance of molecular effects for the identification of a mode of action or an adverse outcome pathway is undisputed, their impact for other regulatory purposes remains uncertain. Here, we report the results of a 28-day rat-feeding study including three widely used hepatotoxic (tri)azole fungicides (cyproconazole, epoxiconazole and prochloraz) administered individually at five dose levels, ranging from slightly above the reference values to a clear toxic effect dose. Parameters analysed included pathology, histopathology, clinical chemistry and particularly effects on the molecular level. Since azole fungicides are considered to cause liver toxicity by a mechanism involving the constitutive androstane receptor (CAR), a known CAR activator (phenobarbital, PB) was administered to investigate potential similarities between triazoles and PB-mediated liver toxicity by pathway-focused gene expression analysis. Our results show an increase in liver weights and additionally histopathological changes (hepatocellular hypertrophy) for all substances at the top dose levels. The effects on liver weight were most pronounced for cyproconazole by which also the animals receiving the next lower dose were affected. In addition, vacuolisation of hepatocytes was observed at the top dose level. No such findings were obtained with any substance at lower doses to which consumers and operators might be exposed to. In contrast, the expression of sensitive marker genes (like some cytochrome-P-450 isoforms) was significantly affected also at the lower dose levels. While some of these changes, like the induction of genes related to fatty acid and phospholipid metabolism (e.g. Fasn, Fat/Cd36, Ppargc1a) or xenobiotic metabolism (Cyp1a1, Cyp2b1, Cyp3a2), could be associated with high dose effects like hepatocellular vacuolisation or hypertrophy, a histopathological correlate was lacking for others.

show abstract

Dose–response involvement of constitutive androstane receptor in mouse liver hypertrophy induced by triazole fungicides

Cited by 26 publications

References 23 publications

A crucial role of constitutive androstane receptor (CAR) in liver tumor development by imazalil in mice

A crucial role of constitutive androstane receptor (CAR) in liver tumor development by imazalil in mice

Effects of tebuconazole on cytochrome P450 enzymes, oxidative stress, and endocrine disruption in male rats

Hepatotoxic effects of (tri)azole fungicides in a broad dose range

Contact Info

Product

Resources

About