Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver

The bile salt export pump

“…Based on comparison of the molecular weight of rat Bsep expressed in Sf9 cells in comparison to rat canalicular membrane vesicles, it is very likely that Bsep is a glycoprotein [33]. Extensive functional comparison in isolated rat canalicular plasma membrane vesicles and in Sf 9 cell vesicles revealed similar kinetic properties of rat Bsep with K m values of 2.1 μM for taurocholate, 3.8 μM for glycocholate, 3.6 μM for taurochenodeoxycholate, and 6.2 μM for tauroursodeoxycholate [86]. These findings indicate that expression in the Sf 9 cell systems is suitable for functional characterization of various Bsep orthologues from different species.…”

“…These close functional relationships between Bsep of different species are paralleled by amino acid sequence similarities of more than 80%, indicating that functional studies with rat Bsep in isolated canalicular liver plasma membrane vesicles can be extrapolated to human BSEP. In rats, the specificity of Bsep is restricted to monovalent bile salts, whereas no transport of taurolithosulfocholate, leukotriene C4, DNP-SG, estradiol-17β-glucuronide, or GSSG was observed [86]. Recently, rat and human Bsep/BSEP were compared after expression in HEK293 cells and were found to have qualitative comparable transport properties with one exception: Human BSEP transported taurolithocholate 3-sulfate significantly, whereas virtually no transport was observed with rat Bsep [38].…”

“…After the cloning of rat Bsep, it was possible to directly test the inhibition of Bsep expressed in Sf 9 cells in the absence of other organic anion transporters. These studies showed that cyclosporine A as well as glybenclamide, rifampicin, and rifamycin are competitive inhibitors of Bsep [86]. The same drugs also inhibit human BSEP [9,72].…”

“…Since the substrate binding site(s) of the various Bsep isoforms is unknown at present, it cannot be excluded that inhibitory drugs are also potential transport substrates of Bsep. Very interestingly, estradiol-17β-glucuronide, a cholestat-ic metabolite of estrogen, requires coexpression of Mrps for inhibition of Bsep [1,86]. This has been interpreted as so-called trans-inhibition since estradiol-17β-glucucronide needs to be transported into the canalicular lumen before it can exert its cholestatic action on Bsep.…”

The multiple facets of ABCB4 (MDR3) deficiency

“…Estrogens are known to induce cholestasis in experimental models of cholestasis 46 . Estrogens decrease uptake of bile acids at the hepatocyte basolateral membrane and inhibit expression of the canalicular bile salt export pump 47 . Increased sulfated progesterone metabolite levels are evident in patients with ICP 46 .…”