Chlorpromazine, Administered in Vivo and in Vitro, Inhibits the Efflux of Bile Acids in Freshly Isolated Rat Hepatocytes*

Abstract

Although it has been speculated that chlorpromazine may alter the transhepatic movement of bile acids from plasma to bile, the effect of chlorpromazine on various determinants of bile acid transport in isolated rat hepatocytes remains incompletely defined. In particular, there is little information about the effect of chlorpromazine on the release of bile acids from freshly isolated hepatocytes. Therefore, we examined the effect of chlorpromazine, administered in vivo and in vitro, on the efflux rate of radiolabeled bile acids in freshly isolated rat hepatocytes. In an isolated haptocyte system, it is not possible to distinguish the sinusoidal plasma membrane function of efflux (back diffusion) from the canalicular plasma membrane function of excretion. Therefore, efflux, as used in this manuscript, reflects both back diffusion and excretion. In vitro, chlorpromazine produced a rapid dose dependent significant (P less than 0.05) decrease of the bile acid efflux rate in freshly isolated hepatocytes. This decrease in bile acid efflux was observed at chlorpromazine concentrations which did not alter hepatocyte plasma membrane permeability (viability), as measured by intracellular potassium content, release of lactate dehydrogenase, and trypan blue exclusion. Moreover, in freshly isolated hepatocytes from chlorpromazine pretreated rats, a significant (P less than 0.05) decrease in the bile acid efflux rate was also observed, and this decrease in efflux was similar in magnitude to the decrease in bile acid efflux observed following exposure of freshly isolated hepatocytes to chlorpromazine in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Transport of organic anions in the liver. An update on bile acid, fatty acid, monocarboxylate, anionic amino acid, cholephilic organic anion, and anionic drug transport

“…However, also with isolated cells it is uncertain to localize efflux phenomena to a distinct cell pole. The efflux from isolated cells was decreased when the cells were prepared from rat livers of cholestatic animals, achieved either by bile duct ligation or ethinylestradiol treatment (Tarao et al 1982), and when rats were pretreated by the cholestatic compound chlorpromazine (Willson et al 1989). This indicates that cholestatic cell perturbations prevail even during the isolation procedure, and that single cells may be used in cholestasis research.…”

Cholangiocyte organoids to study drug-induced injury

“…Therefore, hepatotoxicity by CPZ represents a realistic health risk for humans which should not be ignored [ 13 ]. Experimental studies revealed that CPZ inhibits bile flow in perfused rat livers [ 14 ] and freshly isolated rat hepatocytes [ 15 ], a mechanism associated with bile acid accumulation which likely contributes to cholestasis in animals and humans [ 16 ]. Furthermore, CPZ-induced hepatotoxicity involves the sustained activation of the c-Jun N-terminal kinases (JNKs) pathway of cellular stress [ 17 ], oxidative stress [ 18 ], cell-to-cell junction disruption and release of pro-inflammatory cytokines [ 19 ].…”

Cholangiocyte Organoids to Model Chlorpromazine-Induced Bile Duct Injury

“…Therefore, hepatotoxicity by CPZ represents a realistic health risk for humans which should not be ignored [13]. Experimental studies revealed that CPZ inhibits bile ow in perfused rat livers [14] and freshly isolated rat hepatocytes [15], a mechanism associated with bile acid accumulation which likely contributes to cholestasis in animals and humans [16]. Furthermore, CPZ-induced hepatotoxicity involves the sustained activation of the c-Jun N-terminal kinases (JNKs) pathway of cellular stress [17], oxidative stress [18], cell-to-cell junction disruption and release of pro-in ammatory cytokines [19].…”