Liver hepatotoxic chemicals

Liver cancer can also be a consequence of exposure to hepatotoxic chemicals. Natural hepatocarcinogens include fungal aflatoxins. Synthetic hepato-carcinogens include nitrosoamines, certain chlorinated hydrocarbons, polychlorinated biphenyls (PCBs), chloroform, carbon tetrachloride, dimethyl-benzanthracene, and vinyl chloride.Table 5.15 lists the chemical compounds that induce liver cancer or cirrhosis in experimental animals or... 

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). 

Miyashita, T., Takeda, A., Iwai, M. Shimazu, T. (1991) Single administration of hepatotoxic chemicals transiently decreases the gap-junction-protein levels of connexin32 in rat liver. Eur. J. Biochem., 196, 37-42... 

Billings, R.E. Colorado State University Mechanisms of toxic chemical interaction in the liver-hepatotoxicity NIEHS... 

Hepatotoxic chemicals cause liver damage, jaundice, and liver enlargement. Nephrotoxic chemicals cause kidney damage and renal failure. Hematopoietic chemicals interfere with the production of red blood cells and can cause anemia and leukemia. 

Hepatic Fibrosis/Cirrhosis Fibrosis usually results from chronic inflammation which can be the result of continuous exposure to a variety of hepatotoxic chemicals such as organic arscnicals, vinyl chloride, or high doses of vitamin A (Zimmerman, 1999), chronic ethanol ingestion and nonalcoholic fatty liver disease. Fibrosis usually occurs around the portal area, in the space of Disse, and around the central veins. This results in loss of liver architecture and function. The hepatocytes are replaced with fibrous material and thus there is hepatocyte loss. Periportal fibrosis may lead to portal hypertension. 

Maeda, S., Takeda, S., I> yamoto, Y., Aburada, M., Harada, M. Effects of Gomisin A on liver functions in hepatotoxic chemicals-treated rats. Jpn. J. Pharmacol. 1985 38 347-353... 

Numerous studies have been carried out on the effects of single chemicals on the liver, of which ethanol and carbon tetrachloride are the most notorious. [4,81 Other hepatotoxic chemicals, however, have also been widely studied, both in the laboratory and environmentally. For example, an outbreak of toxic liver disease was reported in a fabric coating company. Upon investigation, it was found that dimethylformamide, a known hepatotoxin, was used as a coating solvent in poorly ventilated areas without appropriate skin protection, and no other hepatotoxins were identified. 1121... 

S Maeda, S Takeda, Y Miyamoto, M Aburada, M Harada. Effect of gomisin A on liver function in hepatotoxic chemicals-treated rats. Japan J Pharmacol 38 347-353, 1985. 

The influence or effects of L-tryptophan administration on the livers of animals pretreated or posttreated with hepatotoxic chemicals or drugs have been investigated in many studies. Selected studies with a number of commonly used toxic agents are cited. The review deals mainly with biochemical changes rather than with morphologic changes. 

Schizandra fruits, has been shown to improve liver injuries caused by hepatotoxic chemicals (e.g., CCI4) and other biphenyl lignans, such as schizandrin 110 and isoschizandrin 111, exhibit inhibitory effects on stress induced gastric-ulceration (106). 

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). 

Delaney, B. and Kaminski, N.E., Liver-immune interactions induced by hepatic regeneration similarities between partial hepatectomy and chemically mediated hepatotoxicity, in Experimental Immunotoxicology, Smialowicz, R J. and Holsapple, M.P., Eds., CRC Press, Boca Raton, 1996. 

Zimmerman, H., Hepatotoxicity The adverse effects of drugs and other chemicals on the liver. (2nd ed.) Philadelphia Lippincott Williams Wilkins, 1999. 

Liver disease may decrease hepatic metabolism resulting in enhanced responses to parent chemicals however, for many compounds, metabolism is only slightly impaired in moderate to severe liver disease. Disease-induced alterations in clearance and volume of distribution often act in opposite directions with respect to their effect on half-life. Bioavailability may be markedly increased in liver disease with portal/systemic anastomosis (the connection of normally separate parts so they intercommunicate) so that orally administered chemicals bypass hepatic first-pass metabolism. Altered receptor sensitivity has been observed for some chemical substances in liver cirrhosis. When liver tissue repair is inhibited by chemical co-exposure, even an inconsequential level of liver injury may lead to fulminating liver failure from a nonlethal exposure of hepatotoxic-ants. (Several articles, as reviewed by Dybing and Spderlund 1999.)... 

The best clinical evidence that BSEP is involved in hepatotoxicity is provided by human genetic studies which found four highly conserved non-synonymous mutations in two hepatobiliary transporters (BSEP and MDR3) that were specific for drug-induced liver injury [118]. Recently, a consortium of investigators identified a remarkable 82 different ABCBll mutations in 109 families that caused severe BSEP deficiency [119]. It is therefore expected that at least some of these genetic mutations and polymorphisms will put patients at an increased risk of drug-induced cholestasis. Does this justify the implementation of a simple BSEP inhibition screen for all new chemical entities The answer is not quite that simple. 

Comparative Toxicokinetics. Metabolic pathways and mechanisms of hepatotoxicity of carbon tetrachloride have been the subject of many studies in intact animals and in vitro, and are therefore better understood than for many other chemicals. However, there are apparently no data on metabolism of carbon tetrachloride in humans. It would be valuable to conduct in vitro experiments with human liver samples and hepatocytes to determine whether metabolic pathways and toxic metabolites are similar to those found in animals. It would also be beneficial to identify an animal model in which MFO systems develop in uteroas they do in the human fetus. 

Bioactivation is a classic toxicity mechanism where the functional group or the chemical structure of the drug molecule is altered by enzymatic reactions. For example, the enzymatic breakdown of the analgesic acetaminophen (paracetamol), where the aromatic nature and the hydroxyl functionality in paracetamol are lost, yields A -acetyl-p-benzoquinone imine, a hepatotoxic agent. Paracetamol can cause liver damage and even liver failure, especially when combined with alcohol. 

An example of a structural substituent that is often metabolized (bioactivated) to an electrophile is the allyl alcohol substituent (C=C—C—OH). Allyl alcohol moieties are found in many commercial chemical substances, either as the free alcohol or as an ester or ether. As illustrated in Scheme 4.1, allyl alcohols (and also as their esters or ethers) that contain at least one hydrogen atom on the alcoholic carbon can be oxidized in the liver by alcohol dehydrogenase (ALDH) to the corresponding a, 3-unsaturated carbonyl metabolite, which is toxic in many cases [29-31]. The hepatotoxicity of allyl alcohol (1), for example, is due to its oxidation by ALDH to acrolein (2), an a,(3-unsaturated aldehyde, which undergoes Michael addition with cellular nucleophiles in the liver [29] (Scheme 4.1). Cyclic allyl alcohols (Scheme 4.1) are expected to undergo similar enzymatic oxidation to yield a,(3-unsaturatcd carbonyl metabolites and are also likely to be toxic. 

Zimmerman HJ. Hepatotoxicity The Adverse Effects of Drugs and Other Chemicals on the Liver. 2nd ed. Lippincott-Williams Wilkins, 1999. 

Bruccoleri, A., Gallucci, R., Germolec, D.R., Blackshear, P, Simeonova, P, Thurman, R.G. Luster, M.I. (1997) Induction of early-immediate genes by tumor necrosis factor a contribute to liver repair following chemical-induced hepatotoxicity. Hepatology, 25, 133-141... 

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