Hepatotoxicity bile salts

Funk, C., Ponelle, C., Scheuermann, G., Pantze, M., Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat, Mol. Pharmacol. 2001, 59, 627-635. 

Liver injury is clinically defined as an increase of serum alanine amino transferase (ALT) levels of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of normal [4]. The clinical patterns of liver injury can be characterized as hepatocellular (with a predominant initial elevation of ALT), cholestatic (with an initial elevation of alkaline phosphatase) or mixed. The mechanisms of drug-induced hepatotoxicity include excessive generation of reactive metabolites, mitochondrial dysfunction, oxidative stress and inhibition of bile salt efflux protein [5]. Better understandings of these mechanisms in the past decades led to the development of assays and models suitable for studying such toxic mechanisms and for selecting better leads in the drug discovery stage. 

Ursodiol is practically free of serious adverse effects. Bile salt-induced diarrhea is uncommon. Unlike its predecessor, chenodeoxycholate, ursodiol has not been associated with hepatotoxicity. 

BSEP — Troglitazone Bosentan Hepatotoxicity due to intracellular accumulation of bile salts... 

The core tests should include those for hepatocellular and cholestatic injury because both or either may occur. Given that it is not always possible to predict whether a xenobiotic will cause either cellular or hiliary injury, the choice of enzymes and bilirubin/bile salts needs to include markers for both of these types of toxicity and to take into consideration the intracellular locations of these enzymes. These common tests are far more effective when used in groups, and reliance should not he placed on any single test for the diagnosis of hepatotoxicity. The recognition of an increase in several of these test values and a pattern of changes offer more evidence of an adverse effect due to a xenobiotic. 

The estrogen receptor-subtype ERa mediates the hepatotoxicity of 17a-ethinylestradiol (EE2). Upon EE2 treatment, ERa represses the expression of bile acid and cholesterol transporters (bile salt export pump, BSEP), Na /taurocholate cotransporting polypeptide (NTCP), OATPl, OATP2, ABCG5, and ABCG8 in the liver [101]. The genetic variability of some of these transporters is well known and could explain, at least in part, the interindividual differences for the tolerability of oral contraceptives. 

Troglitazone sulfate (Ml, the main metabolite) undergoes biliary excretion and accounts for up to 85% of the dose in humans (Loi et al. 1999). In patients with hepatic impairment, troglitazone sulfate was found to accumulate about fourfold in plasma with a threefold increased half-life (Ott et al. 1998 Loi et al. 1999). This metabolite also inhibited the canalicular bile salt export pump (Bsep), organic anion transporting polypeptide (OATP) transporters as well as drug transporters, suggesting it contributes to the hepatotoxicity. 

Neomycin is a polybasic, poorly absorbed antibiotic which forms insoluble precipitates with bile salts (99). It lowers serum cholesterol concentrations in man (100-102) and chickens (99) and increases fecal bile acid excretion. It inhibits the hepatotoxic effects of lithocholic acid ingestion in chickens (99) and prevents bacterial conversion of cholate to deoxycho-late (103). Neomycin, 6-12 g/day, induces a malabsorption syndrome, with mucosal changes similar to those of sprue (104). Bile salt metabolism is thus affected in at least three ways by neomycin (1) a binding effect similar to that of cholestyramine, (2) suppression of deconjugation and secondary bile formation caused by antimicrobial properties, and (3) possible impairment of absorption of bile salts by intestinal mucosa. The first probably accounts for most of the increased fecal excretion of bile salts. 

Profiling of elevated plasma coneentrations of bile acids provides evidence of functional inhibition of bile salt clearance in vivo. This has been observed in rats exposed to a variety of drugs that inhibit BSEP activity in vitro, and in some instances also in humans (Fattinger et al., 2001), which snggests that evalnation of plasma (or serum) bile acids could provide a useful noninvasive biomarker of in vivo BSEP inhibition. However, since uptake carriers on the basolateral plasma membrane domain mediate hepatic nptake of bile acids and therefore also play important roles in bile acid clearance (Kullak-Ublick et al., 2004), potential interactions involving these transporters need to be considered when interpreting effects of compounds on plasma bile acid concentrations. In addition, elevated bile acid concentrations have been observed in plasma and urine from rats treated in vivo with a variety of hepatotoxic drugs, some of which do not inhibit BSEP (e.g., acetaminophen, carbam-azepine Yamazaki et al., 2013). Therefore while elevated total plasma bile acid levels can provide a nseful indirect index of impaired in vivo BSEP-mediated bile salt clearance, they may also arise due to other mechanisms and so cannot be considered a specific in vivo BSEP inhibition biomarker. 

Rodrigues AD, Lai Y, Cvijic ME, EUdn LL, Zvyaga T, Soars MG (2014). Drug-induced perturbations of the bile acid pool, cholestasis, and hepatotoxicity mechanistic considerations beyond the direct inhibition of the bile salt export pump. Drug Metab Dispos 42, 566-74. 

Liver A case of a 61-year-old female who developed acute severe hepatitis following a 16-week therapy of sitaxsentan at 100 mg daily has been reported [31 ]. Despite withdrawal of therapy, her liver tests failed to improve after 6 weeks of follow-up. She however showed clinical and biochemical improvement when a high dose of corticosteroid was administered. The authors thus opined that an immxme-mediated mechanism as opposed to an inhibition of the bile salt transport is the pathway through which sitaxsentan causes hepatotoxicity. 

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