Hepatotoxic mixtures

Pessayre D, Cobert B, Decatoire V, et al. 1982. Hepatotoxicity of trichloroethylene-carbon tetrachloride mixtures in rats. Gastroenterology 83 761-772. 

The best evidences are studies from preclinical animal models [86, 87, 105], or knockout animals lacking appropriate anti-oxidative pathways [106]. For example, Balb/c mice administered a variety of anti-oxidants in their chow were protected from acetaminophen hepatotoxicity [107]. Rats fed with the anti-oxidant melatonin were protected from cholesterol mediated oxidative liver damage [108]. The best clinical evidence that oxidative stress is a key player in a variety of liver injury diseases is the beneficial application of silymarin in these disease indications [109]. Silymarin is a polyphenolic plant fiavonoid (a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin and silichristin) derived from Silymarin maria-num that has antioxidative, antilipid peroxidative, antifibrotic and anti-inflammatory effects [109, 110]. 

Haloalkanes. Certain haloalkanes and haloalkane-containing mixtures have been demonstrated to potentiate carbon tetrachloride hepatotoxicity. Pretreatment of rats with trichloroethylene (TCE) enhanced carbon tetrachloride-induced hepatotoxicity, and a mixture of nontoxic doses of TCE and carbon tetrachloride elicited moderate to severe liver injury (Pessayre et al. 1982). The researchers believed that the interaction was mediated by TCE itself rather than its metabolites. TCE can also potentiate hepatic damage produced by low (10 ppm) concentrations of carbon tetrachloride in ethanol pretreated rats (Ikatsu and Nakajima 1992). Acetone was a more potent potentiator of carbon tetrachloride hepatotoxicity than was TCE, and acetone pretreatment also enhanced the hepatotoxic response of rats to a TCE-carbon tetrachloride mixture (Charbonneau et al. 1986). The potentiating action of acetone may involve not only increased metabolic activation of TCE and/or carbon tetrachloride, but also possible alteration of the integrity of organelle membranes. Carbon tetrachloride-induced liver necrosis and lipid peroxidation in the rat has been reported to be potentiated by 1,2- dichloroethane in an interaction that does not involve depletion of reduced liver glutathione, and that is prevented by vitamin E (Aragno et al. 1992). 

Antihepatotoxic activity. A mixture of the methanol-insoluble fraction of the dried resin, fresh garlic, curcumin, ellagic acid, butylated hydroxytoluene, and butylated hydroxyanisole, administered by gastric intubation to ducklings at a dose of 10 mg/ani-mal, was active vs aflatoxin Bl-induced hepatotoxicity " . ... 

Hepatotoxicity was observed in rats and mice chronically exposed by gavage to a mixture of 1,2,3,6,7,8-HxCDD and 1,2,3,7,8,9-HxCDD (NCI/NTP 1980). Liver effects were also found in rats exposed by diet toHpCDD (Viluksela et al. 1994), 1,2,3,7,8-PeCDD and 1,2,3,4,7,8-HxCDD (Viluksela et al. 1998b), and OCDD for subchronic durations (Bimbaum et al. 1989a Couture et al. 1988), and to 2,7-DCDD for a... 

In the study of Teuschler et al. (2000), the models for analyzing the data were selected beforehand, and it was also decided to only focus on environmentally relevant mixtures. The authors indicated that these 2 factors were decisive for choosing the concentration levels to test. The concentration levels were not selected in relation to a specific endpoint, using the toxic unit approach. This may have been avoided because several different hepatotoxic endpoints have been measured simultaneously. The concentrations tested enabled the use of 3 types of models a multiple regression CA model, the interaction-based HI, and the proportional-response addition method. A major problem with mixture toxicity research in general is the... 

Mehendale HM. 1994. Mechanism of the interactive amplification of halomethane hepatotoxicity and lethality by other chemicals. In Yang RSH, editor, Toxicology of chemical mixtures case studies, mechanisms, and novel approaches. San Diego (CA) Academic Press, p 299-334. 

It is difficult to clarify the hepatotoxicity of herbal remedies, especially if they are comprised of a mixture of several plants or various components of the plant. Moreover, herbal remedies are often applied as automedication, and patients withhold the information that they have used them. (s. tab. 29.9) (s. fig. 29.15)... 

Atrium, a proprietary mixture of phenobarbital, febar-bamate, and difebarbamate, has caused several cases of hepatotoxicity, at least one of which was ascribed to the carbamates, because the patient had earlier tolerated phenobarbital (SEDA-18, 74). Atrium-induced hepatitis might be facilitated by defective CYP2C19 activity (SEDA-19, 77). 

Tsumura, a Japanese herbal mixture has been associated with hepatotoxicity (179). 

The UK hepatologists have described two cases of severe liver damage, one fatal, attributed to Chinese herbal mixtures for minor complaints (28). D. dasycarpus was implicated in one. There have been other reports of hepatotoxicity due to D. dasycarpus (28). 

Flowever, ampelopsin C and the mixture of (-i-)-vitisin A (698) and (+)-cw-vitisin A (702) were found to be powerful hepatotoxins. The coexistence of hepatoprotective and hepatotoxic agents in the same plant is very interesting, and the plant has been used to cure hepatic diseases such as hepatitis and liver cirrhosis [519]. 

Artificial vanilla flavoring is a solution of pure synthesized vanillin, 4-hydroxy-3-methoxybenzaldehyde. Mixtures of vanillin with other toxicants enhance mutagenic effects 31 and produce synergistic inhibition of lignocellulose degradation when mixed with catechol. 32 Vanillin potentiates the hepatotoxicity of carbon tetrachloride. 331 Mixtures of vanillin and cigarette smoke condensates induce sister-chromatid exchanges. 34 ... 

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