Hepatotoxic effect

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

Potential hepatotoxic effects of various brominated benzenes, however, should be considered. Bromobenzene which is a monobrominated compound, is used in various experiments as a model hepatotoxic compound (refs. 9-11). 

The purpose of this study was to compare hepatotoxic effects of monobromo-benzene, 3 dibromobenzene isomers, hexabromobenzene and tetrabromobisphenol A with special attention paid to the dynamics of changes of selected indicators of liver necrosis during acute poisoning. 

Secchi GC, Chiappino G, Lotto A, et al. 1968. [Acutal chemical composition of commercial trilenes and their hepatotoxic effects Clinical and enzymological study.] Med Lav 59(8-9) 486-497. 

Venugopal, N.B.R.K. and S.L.N. Reddy. 1992b. Nephrotoxic and hepatotoxic effects of bivalent and hexavalent chromium in a teleost fish Anabas scandens enzymological and biochemical changes. Ecotoxicol. Environ. Safety 24 287-293. 

Chlordane interacts with other chemicals to produce additive or more-than-additive toxicity. For example, chlordane increased hepatotoxic effects of carbon tetrachloride in the rat (USEPA 1980 WHO 1984), and in combination with dimethylnitrosamine acts more than additively in producing liver neoplasms in mice (Williams and Numoto 1984). Chlordane in combination with either endrin, methoxychlor, or aldrin is additive or more-than-additive in toxicity to mice (Klaassen et al. 1986). Protein deficiency doubles the acute toxicity of chlordane to rats (WHO 1984). In contrast, chlordane exerts a protective effect against several organophosphorus and carbamate insecticides (WHO 1984), protects mouse embryos against influenza virus infection, and mouse newborns against oxazolone delayed hypersensitivity response (Barnett et al. 1985). More research seems warranted on interactions of chlordane with other agricultural chemicals. 

Fenvalerate inhibits intercellular communication between fibroblast cells and enhances the development of hepatocyte foci in rat liver at nonhepatotoxic dose levels. Chemicals that possess these properties are likely to be tumor promoters (Flodstrom et al. 1988). Fenvalerate alone induced no hepatotoxic effects in rat liver, as judged by transaminase activities and histology. However, some rats that were partially hepatectomized and insulted with nitrosodiethylamine — a carcinogen and tumor initiator — had significantly elevated numbers of liver foci after administrations of fenvalerate. This response suggests that fenvalerate is a potential tumor promoter (Flodstrom et al. 1988). 

Testosterone can be replaced orally, parenterally, or transdermally (see Table 83-2). Injectable regimens are preferred because they are effective, are inexpensive, and do not have the bioavailability problems or adverse hepatotoxic effects of oral regimens. Testosterone patches and gel are more expensive than other forms and should be reserved for patients who refuse injections. 

Kendall MW. 1974a. Acute hepatotoxic effects of mirex in the rat. Bull Environ Contam Toxicol 12(5) 617-621. 

Di-n-octy lphthalate has been shown to be a liver toxin at high doses in acute- and intermediate-duration animal studies. Di-n-octylphthalate does not appear to behave like other phthalate esters, such as di(2-ethylhexyl)phthalate, which have been shown to be hypolipidemic peroxisome proliferators. Rather, its effects on the liver are more characteristic of other "classic hepatotoxins" (Lake et al. 1984, 1986 Mann et al. 1985). However, the specific mechanism(s) of action for inducing the hepatotoxic effects of di-n-octylphthalate is not known. Therefore, there are currently no methods available for interfering with the mechanism of action for the toxic effects of di -n-octylphthalate. 

Interesting information stems from studies of the hepatotoxic effect of the concomitant administration of rifampicin, another antituberculostatic drug (and a potent inducer of cytochrome P450) often used in combination with isoniazid. Rifampicin alone is not hepatotoxic but increases significantly the incidence of hepatitis in patients simultaneously dosed with isoniazid. In human volunteers (6 slow and 8 rapid acetylators), daily administration of rifampicin increased the release of hydrazine from isoniazid [180], In slow acetylators, the proportion of the dose metabolized to hydrazine increased... 

Dibromoethane did not potentiate the hepatotoxic effects of carbon tetrachloride in rats (Danni et al. 1988). 

The MRL was based on a LOAEL of 14 ppm in workers exposed to concentrations of chloroform of up to 400 ppm for less than 6 months (Phoon et al. 1983). Vomiting and toxic hepatitis were noted to occur at an inhaled chloroform concentration of 14 ppm. The LOAEL of 14 ppm was divided by an uncertainty factor of 100 (10 for the use of a LOAEL and 10 for human variability) and a modifying factor of 3 (insufficient diagnostic data to determine the seriousness of hepatotoxic effects) to arrive at the MRL of 0.05 ppm. Alterations in liver functions have been reported in several studies in both humans and animals, and is discussed in more detail in the chronic-duration inhalation MRL section immediately below. 

Several animal studies indicate that chloroform interacts with other chemicals within the organism. The lethal and hepatotoxic effects of chloroform were increased by dicophane (DDT) (McLean 1970) and phenobarbital (a long-acting barbiturate) in rats (Ekstrom et al. 1988 McLean 1970 Scholler 1970). Increased hepatotoxic and nephrotoxic effects were observed after interaction with ketonic solvents and ketonic chemicals in rats (Hewitt and Brown 1984 Hewitt et al. 1990) and in mice (Cianflone et al. 1980 Hewitt et al. 1979). The hepatotoxicity of chloroform was also enhanced by co-exposure to carbon tetrachloride in rats (Harris et al. 1982) and by co-exposure to ethanol in mice (Kutob and Plaa 1962). Furthermore, ethanol pretreatment in rats enhanced chloroform-induced hepatotoxicity (Wang et al. 1994) and increased the in vitro metabolism of chloroform (Sato et al. 1981). 

In a series of experiments, Eldridge et al. (1992) studied the acute hepatotoxic effects of 1,4-dichlorobenzene and the role of cell proliferation in hepatotoxicity in B6C3F, mice and Fischer 344 rats. Mice and rats received a single dose of 1,4-dichlorobenzene by gavage in com oil of 600, 900, or... 

Extracts of toxic isolates of M. aeruginosa or a purified peptide toxin injected into the bloodstream or the peritoneal cavity of mice elicit hepatotoxic effects (5-7,8). The fresh weight of the liver is greatly increased, and sinusoidal congestion, hemorrhage, and necrosis of the liver are observed. A lethal dose of purified toxin also induces multiple thrombi in the lungs and causes a marked reduction in the number of circulating blood platelets (6,7). 

Hepatotoxic effects, such as elevated GGT levels and small alterations in lipid profile, have sometimes been observed in humans after exposure to high 2,3,7,8-TCDD levels. In general, the effects have been mild and in some cases appear to have been transient."... 

Reichert D, Henschler D, Bannasch P Nephrotoxic and hepatotoxic effects of dichloroacetylene. Food Cosmet Toxicol 16 227-235, 1978... 

Naltrexone is contraindicated in acute hepatitis or liver failure. Carefully consider its use in patients with active liver disease in light of its hepatotoxic effects. 

The hepatotoxic effects of carbon tetrachloride have been widely studied in animals. Indeed, carbon tetrachloride is used as a model chemical in many laboratory investigations of the basic mechanism of action of hepatotoxic chemicals. Oral exposure to carbon tetrachloride has been observed to result in a wide spectrum of adverse effects on the liver, the most prominent of which are destruction of the smooth and rough endoplasmic reticulum and its associated enzyme activities (Reynolds and Yee 1968), inhibition of protein synthesis (Lutz and Shires 1978), impaired secretion of triglycerides with resultant fat accumulation (Fischer-Nielsen et al. 1991 Recknagel and Ghoshal 1966 Recknagel and Glende 1973 Waterfield et al. 1991), centrilobular necrosis (Blair et al. 1991 Reynolds and Yee 1968 Waterfield et al. 1991 Waterfield et al. 1991 Weber et al. 1992), and eventually fibrosis and cirrhosis (Allis et al. 1990 Bruckner et al. 1986 Fischer-Nielsen et al. 1991 Weber etal. 1992). 

Cholestatic hepatitis may occur when drug therapy lasts longer than 10 days or repeated courses are prescribed. The hepatitis is characterized by fever, enlarged and tender liver, hyperbilirubinemia, dark urine, eosinophilia, elevated serum bilirubin, and elevated transaminase levels. Hepatitis has been associated with the estolate salt of erythromycin but not with other formulations. Although the hepatitis usually occurs 10 to 20 days after the initiation of therapy, it can occur within hours in a patient who has had such a reaction in the past. The hepatitis is believed to be the result of both a hepatotoxic effect and a hypersensitivity reaction this latter effect is reversible on withdrawal of the drug. Erythromycin and derivatives induce hepatic microsomal enzymes and interfere with the actions of various drugs, including theophylline and carbamazepine. 

BoverhofDRet al (2006) Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice. Toxicol Sci 94 398-116. doi kfll 00 (pii) 10.1093/toxsci/kfl 100... 

Watkins PB, Zimmerman HJ, Knapp MJ, et al Hepatotoxic effects of tacrine administration in patients with Alzheimer s disease. JAMA 271 992-998, 1994... 

Drug interactions Proleukin may affect central nervous system function. Therefore interactions could occur following concomitant administration of psychotropic drugs. Concurrent administration of drugs possessing nephrotoxic, myelotoxic, cardiotoxic, or hepatotoxic effects with Proleukin may increase toxicity in these organ systems. Reduced kidney and liver function secondary to Proleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs. Beta-blockers and other antihypertensives may potentiate the hypotension seen with Proleukin. 

In one-, four- and 13-week studies, the effects of coumarin treatment were compared in male Sprague-Dawley rats, CD-I mice and Syrian hamsters. Rats were fed 0-0.75% coumarin for one and four weeks and 0.5% coumarin for 13 weeks. Mice and hamsters were fed 0-0.5 and 0-1.0% coumarin, respectively, for one, four or 13 weeks. In the rat, coumarin caused dose-related hepatotoxic effects which included vacuolar degeneration, apoptosis and bile duct proliferation and increases in serum bilirubin content and both serum and hepatic y-glutamyltranspeptidase activity. A sustained stimulation of hepatocyte replicative DNA synthesis was observed in rats treated for four and 13 weeks. Levels of total hepatic glutathione were increased approximately twofold, and there were statistically significant decreases in microsomal cytochrome P450 content and ethylmorphine 7V-demethylase activity. These effects were reduced or not observed in mice and hamsters (Lake Grasso, 1996). 

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