Hepatotoxicity chemical-induced liver injury

Chemical-induced liver injury is differentially modified by diabetes in murine type 1 diabetic models. Contrary to the enhanced hepatotoxicity in diabetic rats, diabetes in mice tends to protect animals from severe hepatotoxicity. It has been reported that the induction of diabetes in Swiss mice did not increase the susceptibility of mice to CCI4 hepatotoxicity as occurs in rats. Development of diabetes also protected mice from acetaminophen toxicity. Further studies also showed that streptozotocin-induced diabetic mice were substantially resistant to lethal doses... 

Hepatotoxicity was reported in an elderly man who had been taking an herbal stimulant laxative for many years. The hepatotoxicity appeared shortly after the laxative was reformulated to contain boldo (Piscaglia et al. 2005). An animal study reported a protective effect of boldo against chemical-induced liver injury (Lanhers et al. 1991). 

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. 

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.)... 

Strieker BHCH (1992) Drug-induced Hepatic Injury, 2nd edn. Amsterdam Elsevier Science. Zimmerman Hj (ed) (1999) Hepatotoxicity The adverse effects of drugs and other chemicals on the liver. Philadelphia Lippincott Williams Wilkins. 

Kidneys have relatively low xenobiotic-metabolizing enzyme activities, and chemically induced nephrotoxicity has been assumed to be produced by toxic intermediates generated in the liver and transported to the kidney. If a single hepatic metabolite of chloroform produced both kidney and liver injury, species, strain, and sex differences in susceptibility to chloroform nephro- and hepatotoxicity should be similar. However, species, strain and sex differences in susceptibility to chloroform nephrotoxicity are not consistent with those of chloroform hepatotoxicity. In addition, several modulators of tissue xenobiotic-metabolizing activities alter... 

The widespread use of isoniazid prophylaxis for tuberculosis has focused attention on the liver injury caused by this drug. About 20% of patients treated with isoniazid will show elevated blood concentrations of liver enzymes and bilirubin that subside as treatment is continued (25). However/ clinical hepatitis develops in some patientS/ and these reactions can prove fatal. Current understanding of the mechanism of isoniazid-induced hepatotoxicity is based on the metabolic pathways shown in Figure 16.6 (26/ 27). It has been demonstrated in an animal model that hepatotoxicity is correlated with plasma concentrations of hydrazine but not of acetylhydrazine or isoniazid (28)/ and that pretreatment with an amidase inhibitor can prevent toxicity (27). However/ it is postulated that hydrazine is further metabolized to a chemically reactive he pa to toxin by the cytochrome P450 system/ and in vitro studies with hepatocytes have implicated CYP2E1 as the cytochrome P450 isoform responsible for cytotoxic metabolite formation (29). 

MEHENDALE, H.M., ROTH, R.A., GANDOLFI, A.J., KLAUNIG, J.E., LEMASTERS, J.J. and CURTIS, L.R. (1994) Novel mechanisms in chemically induced hepatotoxicity. FASEBJ., 8, 1285. NELSON, S.D. (1995) Mechanisms of the formation and disposition of reactive intermediates that can cause acute liver injury. Drug Metab. Rev., 27, 147. 

Zinunennan (1999a) Drug-induced liver disease. In Schiff E, Sorrell M, Maddrey W (eds) Schiff s diseases of the liver. Lippincott-Raven, Philadelphia, pp 973-1064 Zimmerman HJ (1999b) Hepatotoxicity. The adverse effects of drags and other chemicals on the liver, 2nd edn. Lippicott Williams Wilkins, Philadelphia Zimmerman HJ, Lewis JH, Ishak KG, Maddrey WC (1984) Ticrynafen-associated hepatic injury analysis of 340 cases. Hepatology 4 315-323... 

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). 

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