Mechanisms and in vitro models of drug-induced cholestasis

Abstract

Cholestasis underlies one of the major manifestations of drug-induced liver injury. Drug-induced cholestatic liver toxicity is a complex process, as it can be triggered by a variety of factors that induce 2 types of biological responses, namely a deteriorative response, caused by bile acid accumulation, and an adaptive response, aimed at removing the accumulated bile acids. Several key events in both types of responses have been characterized in the past few years. In parallel, many efforts have focused on the development and further optimization of experimental cell culture models to predict the occurrence of drug-induced cholestatic liver toxicity in vivo. In this paper, a state-of-the-art overview of mechanisms and in vitro models of drug-induced cholestatic liver injury is provided.

Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury

“…This complied with the observations of the present study, which showed suppression of BSEP activity by ATA, NEFA, and CsA in HepaRG cell cultures, albeit no altered gene expression of the transporter was observed. Nevertheless, it should be emphasized that besides BSEP inhibition, other molecular initiating events underlie cholestatic liver injury, including effects on alternative transporters, hepatocellular changes, and bile canalicular changes (Gijbels et al 2019). In this regard, NEFA has been reported to inhibit OATP(s) and multidrug resistance protein 1 (MDR1) transporter (Dragovic et al 2016;Kolaríc et al 2019).…”

“…Therefore, a 50 × concentrated BA mix of the five most abundant BAs present in human serum was added to HepaRG cells together with the cholestatic drugs. This setup enabled more close resemblance to the in vivo situation during cholestasis, to detect BA-selective sensitization towards toxic effect of cholestatic drugs, as well as to distinguish cholestatic hepatotoxicity from non-cholestatic hepatotoxicity (Sharanek et al 2017;Gijbels et al 2019). In this study, the cholestatic drugs ATA, CsA, and NEFA were selected based on literature data (Oorts et al 2016;Rakotondravelo et al 2012).…”

Industrial, Biocide, and Cosmetic Chemical Inducers of Cholestasis

“…These nuclear receptors equally play a key role in cholestasis, in particular by mediating the adverse response and inducing the expression of genes involved in counteracting bile acid accumulation, including those coding for hepatic transporters and biotransformation enzymes. 2,4 Triclosan causes hepatic inflammation 80 , oxidative stress 81 , mitochondrial toxicity 82,83 , cell cycle arrest and apoptosis 81,84 . Triclosan also suppresses microfilament remodeling and cell membrane ruffling 85 , and affects a number of signaling cascades, including protein kinase B 86,87 and extracellular signal-regulated kinases 1/2 87 , all that collectively promote cholestatic liver injury.…”

“…17 In rats, alpha-naphthylisocyanate evokes hepatic inflammation 18 , oxidative stress 14 , endoplasmic reticulum stress 19 and mitochondrial toxicity 20 , all being key events in cholestatic liver injury. 2,4 Alpha-naphthylisocyanate alters the expression and/or activity of a number of hepatic transporters, including the bile salt export pump, multidrug resistance-associated protein 2/3 and multidrug resistance protein 3. [21][22][23] Furthermore, alpha-naphthylisocyanate disrupts hepatic tight junctions 24,25 , decreases membrane fluidity 26 and causes bile canaliculi dilatation 27 .…”

“…28 Alphanaphthylisocyanate actives the farnesoid X receptor and the pregnane X receptor in mouse liver, 29 which mediate the adaptive response in cholestatic injury. [2][3][4] 3 3,5-Diethoxycarbonyl-1,4-dihydrocollidine 3,5-diethoxycarbonyl-1,4-dihydrocollidine ( Figure 2) is a porphyrinogenic agent and a powerful inducer of delta-aminolevulinate synthetase. 30 It has been used since many decades to experimentally induce cholestasis in rodents.…”