Repression of bile salt efflux pump expression by tri-ortho-cresyl phosphate in cultured human hepatic cells

Tri-ortho-cresyl phosphate (TOCP) is an environmental toxic pollutant, belonging to the chemical class of organophosphorus flame retardants and repressing hepatic membrane drug transporter expression. The present study investigated whether the liver canalicular bile salt efflux pump (BSEP) may also be targeted by TOCP. TOCP used at a non-cytotoxic concentration of 10 μM for 48 h was demonstrated to decrease BSEP mRNA expression in cultured hepatic HepaRG cells (by a 4.4-fold factor) and primary human hepatocytes (by a 2.5-fold factor). This effect was concentration-dependent (IC₅₀ = 0.8 μM) and was associated with a significant reduction of canalicular taurocholate secretion in HepaRG cells. It was not impaired by TOCP metabolism inhibitors. TOCP also potently antagonized farnesoid-X-receptor (FXR) mediated-BSEP up-regulation. The specific FXR antagonist DY268 decreased constitutive BSEP expression in HepaRG cells, as TOCP, suggesting a major implication of FXR antagonism in TOCP effects towards BSEP. The TOCP-mediated BSEP repression was finally predicted to potentially occur in vivo in response to a neurotoxic dose or to acute or chronic safe doses of TOCP. Taken together, these data demonstrate that the major bile salt transporter BSEP is a target for TOCP, which may support deleterious hepatotoxic effects of this chemical.