Comparison of the Hepatotoxicity of Coumarin in the Rat, Mouse, and Syrian Hamster: A Dose and Time Response Study

Lake, Brian G.; Grasso, P.

doi:10.1093/toxsci/34.1.105

Cited by 14 publications

(12 citation statements)

References 29 publications

(57 reference statements)

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“…DCB is a nongenotoxic agent (Loeser and Litchfield, 1983;NTP, 1987;Steinmetz et al, 1988), which appears to produce an additive hyperplasia in rodent liver and a regenerative hyperplasia in male rat kidney. While increased cell proliferation has been implicated in the formation of tumors in rodents by various classes of nongenotoxic carcinogens (Loury et al, 1987;Butterworth, 1991;Cohen and Ellwein, 1991;Grasso and Hinton, 1991;Ames et al, 1993;Lake, 1995;Cunningham, 1996;Lake and Grasso, 1996), a correlation between increased cell replication and carcinogenesis is not always observed (Melnick and Huff, 1993;Melnick et al, 1996). In the present study replicative DNA synthesis was increased in both species after acute DCB treatment, whereas in the NTP bioassay DCB produced liver tumors only in the mouse.…”

Section: Discussioncontrasting

confidence: 48%

Comparison of the Hepatic and Renal Effects of 1,4-Dichlorobenzene in the Rat and Mouse

1997

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The effects of 1,4-dichlorobenzene (DCB) have been compared in male F344 rats given 0 (corn oil control), 25, 75, 150, and 300 mg/kg DCB and male B6C3F, mice given 0 (corn oil control), 300, and 600 mg/kg DCB by daily oral gavage five days per week for 1,4, and 13 weeks. The two highest rat and both mouse dose levels were the same as those employed in a NTP bioassay, where DCB produced kidney tumors in male rats and liver tumors in mice. DCB produced significant dose-related increases in relative liver weight in both the rat and the mouse which was associated with, respectively, mild and marked centrilobular hypertrophy. Administration of DCB also produced a sustained induction of microsomal cytochrome P450 content and 7-pentoxyresorufin O-depentylase activity in both species. Western immunoblotting studies demonstrated that DCB induced CYP2B isoenzyme(s) in both rat and mouse liver microsomes. Replicative DNA synthesis was studied by implanting osmotic pumps containing 5-bromo-2'-deoxyuridine in study Weeks 0-1, 3-4, and 12-13. In the rat hepatocyte labeling index values were only increased in animals given 300 mg/kg DCB for 1 week, whereas hepatocyte labeling index values were significantly increased in mice given 300 and 600 mg/kg DCB for 1 and 4 weeks. DCB treatment produced significant increases in rat renal Pi/P 2 proximal tubule cell labeling index values at all time points, whereas little effect was observed in mouse kidney. The observed species difference in DCB-induced liver tumor formation may reflect the greater sensitivity of the mouse to tumor promotion by a CYP2B inducer. For the kidney, the present data provides further evidence that while DCB-induced a 2 irglobulin nephropathy is associated with a sustained stimulation of cell replication in male rat renal proximal tubule cells, this effect is not observed in the male mouse, o 1997 Soda? of Toxicology.1,4-Dichlorobenzene (DCB; CAS 106-46-7) is a volatile organic solid used as a space deodorant, a moth repellent, and as an intermediate in organic syntheses (NTP, 1987). Studies into the metabolism of DCB have indicated that the 'To whom correspondence should be addressed. Fax: 44-(0)181-661-7029.major metabolites are the glucuronide and sulfate conjugates of 2,5-dichlorophenol (Azouz et al., 1955;Hawkins et al, 1980;Klos and Dekant, 1994). Human hepatic cytochrome P450 isoenzymes which can metabolize DCB to 2,5-dichlorophenol include CYP1A2 and CYP2E1 (Bogaards et al, 1995). Studies into the acute toxicity of DCB and its isomers have demonstrated that 1,2-dichlorobenzene is more toxic to rat and mouse liver and to rat kidney than 1,3-dichlorobenzene and DCB (Allis et al, 1992;Valentovic et al., 1993;Umemura et al., 1996).DCB is considered to be a nongenotoxic agent as demonstrated by results of a number of short-term tests for mutagenic and genotoxic potential (Loeser and Litchfield, 1983; NTP, 1987;Steinmetz et al, 1988). The carcinogenicity of DCB has been evaluated in a 2-year study in F344 rats and B6C3F, mice (NTP, 1987). DCB was administere...

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Section: Discussioncontrasting

confidence: 48%

Comparison of the Hepatic and Renal Effects of 1,4-Dichlorobenzene in the Rat and Mouse

1997

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“…21 The pharmacological profiles of coumarin compounds are largely known. [22][23][24] The present study also indicated characteristics of rapid action and full reversibility for the coumarin compounds in activating DF508-CFTR, making coumarins a favourable class of natural lead compounds for the development of therapeutic CF drugs.…”

Section: Discussionsupporting

confidence: 58%

Identification of Natural Coumarin Compounds That Rescue Defective Δf508‐cftr Chloride Channel Gating

Liu

et al. 2008

Clin Exp Pharma Physio

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1. Deletion of phenylalanine at position 508 (DeltaF508) of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is the most common mutation causing cystic fibrosis (CF). Effective pharmacological therapy of CF caused by the DeltaF508-CFTR mutation requires the rescue of both intracellular processing and channel gating defects. 2. We identified a class of natural coumarin compounds that can correct the defective DeltaF508-CFTR chloride channel gating by screening a collection of 386 single natural compounds from Chinese medicinal herbs. Screening was performed with an iodide influx assay in Fischer rat thyroid epithelial cells coexpressing DeltaF508-CFTR and an iodide-sensitive fluorescent indicator (YFP-H148Q/I152L). 3. Dose-dependent potentiation of defective DeltaF508-CFTR chloride channel gating by five coumarin compounds was demonstrated by the fluorescent iodide influx assay and confirmed by an Ussing chamber short-circuit current assay. Activation was fully abolished by the specific CFTR inhibitor CFTR(inh)-172. Two potent compounds, namely imperatorin and osthole, have activation K(d) values of approximately 10 micromol/L, as determined by the short-circuit current assay. The active coumarin compounds do not elevate intracellular cAMP levels. Activation of DeltaF508-CFTR by the coumarin compounds requires cAMP agonist, suggesting direct interaction with the mutant CFTR molecule. Kinetics analysis indicated rapid activation of DeltaF508-CFTR by the coumarin compounds, with half-maximal activation of < 5 min. The activating effect was fully reversed for all five active compounds 45 min after washout. 4. In conclusion, the natural coumarin DeltaF508-CFTR activators may represent a new class of natural lead compounds for the development of pharmacological therapies for CF caused by the DeltaF508 mutation.

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“…Instead, itraconazole and IT-A induced moderate to severe fatty liver in mice. Rats and mice have shown different hepatotoxicity responses to certain compounds, such as coumarin (43). Interstrain differences of hepatotoxicity responses have also been observed in mice treated with cocaine and phenobarbital (44).…”

Section: Discussionmentioning

confidence: 99%

Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole

Shim

Bumpus

et al. 2016

Clinical Cancer Research

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Purpose: Itraconazole is a triazole antifungal drug that has recently been found to inhibit angiogenesis. Itraconazole is a relatively well-tolerated drug but shows hepatotoxicity in a small subset of patients. Itraconazole contains three chiral centers and the commercial itraconazole is composed of four cis-stereoisomers (named IT-A, IT-B, IT-C, and IT-D). We sought to determine whether the stereoisomers of itraconazole might differ in their antiangiogenic activity and hepatotoxicity.Experimental Design: We assessed in vitro antiangiogenic activity of itraconazole and each stereoisomer using human umbilical vein endothelial cell (HUVEC) proliferation and tube formation assays. We also determined their hepatotoxicity using primary human hepatocytes in vitro and a mouse model in vivo. Mouse Matrigel plug and tumor xenograft models were used to evaluate in vivo antiangiogenic and antitumor activities of the stereoisomers.Results: Of the four stereoisomers contained in commercial itraconazole, we found that IT-A (2S,4R,2 0 R) and IT-C (2S,4R,2 0 S) were more potent for inhibition of angiogenesis than IT-B (2R,4S,2 0 R) and IT-D (2R,4S,2 0 S). Interestingly, IT-A and IT-B were more hepatotoxic than IT-C and IT-D. In mouse models, IT-C showed more potent antiangiogenic/antitumor activity with lower hepatotoxicity compared with itraconazole and IT-A.Conclusions: These results demonstrate the segregation of influence of stereochemistry at different positions of itraconazole on its antiangiogenic activity and hepatotoxicity, with the 2 and 4 positions affecting the former and the 2 0 position affecting the latter. They also suggest that IT-C may be superior to the racemic mixture of itraconazole as an anticancer drug candidate due to its lower hepatotoxicity and improved antiangiogenic activity.

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Comparison of the Hepatotoxicity of Coumarin in the Rat, Mouse, and Syrian Hamster: A Dose and Time Response Study

Cited by 14 publications

References 29 publications

Comparison of the Hepatic and Renal Effects of 1,4-Dichlorobenzene in the Rat and Mouse

Comparison of the Hepatic and Renal Effects of 1,4-Dichlorobenzene in the Rat and Mouse

Identification of Natural Coumarin Compounds That Rescue Defective Δf508‐cftr Chloride Channel Gating

Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole

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