Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice

Abstract

We investigated the hepatotoxicity induced by AQ using a glutathione (GSH)-depleted mice model. Although sole administration of either AQ or L-buthionine-S,R-sulfoxinine (BSO), a well-known GSH synthesis inhibitor, produced no significant hepatotoxicity, combined administration of AQ with BSO induced hepatotoxicity characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Pretreatment of aminobenzotriazole, a nonspecific inhibitor for P450s, completely suppressed the above hepatotoxicity caused by AQ co-treatment with BSO. Administration of radiolabeled AQ in combination with BSO exhibited significantly higher covalent binding to mice liver proteins than that observed after sole dosing of radiolabeled AQ. The results obtained in this GSH-depleted animal model suggest that the reactive metabolite of AQ formed by hepatic P450 binds to liver proteins, and then finally leads to hepatotoxicity. These observations may help to understand the risk factors and the mechanism for idiosyncratic hepatotoxicity of AQ in humans.

Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset

“…Covalent binding of AQ in the liver, spleen, gut, and kidney AQ covalently binds proteins in the liver (Shimizu et al, 2009). An anti-AQ antibody was used here to evaluate the extent of covalent binding in different tissues.…”

“…Recently, a model of AQ-induced hepatotoxicity has been reported (Shimizu et al, 2009). However, as with most animal models, this is an acute model of hepatotoxicity in which mice were treated with buthionine sulfoximine and AQ for up to 24 hours, and this resulted in an increase in alanine transaminase (ALT) levels.…”

Hepatic glutathione contributes to attenuation of thioacetamide-induced hepatic necrosis due to suppression of oxidative stress in diet-induced obese mice

“…All of the mice were given either TA (100 mg/kg) or saline once intraperitoneally as described in Experiment 1 (except for mice necropsied at 0 hr), and were necropsied at 1 hr after the 1st BSO treatment (represented as 0 hr after TA treatment) or were necropsied at 3, 8, 24 and 48 hr after the TA or saline administration. To decrease hepatic glutathione, as described previously (Shimizu et al, 2009), all of the mice were given BSO (700 mg/kg body weight; dissolved with saline) or saline twice intraperitoneally, once at 1 hr before and again at 5 hr after TA or saline administration (except for mice necropsied at 0 and 3 hr). Hence, there were 4 groups, vehicle-only treated group (vehicle/ vehicle group), BSO-and vehicle-treated group (BSO/ vehicle group), vehicle-and TA-treated group (vehicle/TA group) and BSO-and TA-treated group (BSO/TA group).…”

“…On the other hand, gamma-glutamylcysteine synthetase is the rate-limiting enzyme of GSH synthesis (Lu, 2000). A specific inhibitor of this enzyme, L-buthionine-S,R-sulfoxinine (BSO), can decrease the GSH level, even in vivo (Watanabe et al, 2003;Shimizu et al, 2009). By investigating hepatic metabolites of GSH synthesis and examining the effect of BSO treatment on hepatic oxidative stress and hepatic necrosis after TA dosing, therefore, we can confirm whether GSH is important in attenuation of TA-induced hepatic necrosis in HFD mice.…”

Role of cytochrome P450-mediated metabolism and identification of novel thiol-conjugated metabolites in mice with phenytoin-induced liver injury

“…in vitro (Gan et al, 2005) in vivo GSH (LPS) (Shaw et al, 2007;Tukov et al, 2007;Lu et al, 2012) LPS GSH (Shimizu et al, 2009;Nishiya et al, 2008 DPH (Dhar et al, 1974;Haruda, 1979;Taylor et al, 1984 (Munns et al, 1997) 4'-HPPH CYP GSH (Munns et al, 1997;Roy and Snodgrass, 1988;1990…”