Interspecies Variability in Expression of Hepatobiliary Transporters across Human, Dog, Monkey, and Rat as Determined by Quantitative Proteomics

Abstract

We quantified, by liquid chromatography tandem mass spectrometry, transporter protein expression of BSEP, MATE1, MRP3, MRP4, NTCP, and OCT1 in our human liver bank (n = 55) and determined the relationship between protein expression and sex, age and genotype. These data complement our previous work in the same liver bank where we quantified the protein expression of OATPs, BCRP, MDR1, and MRP2. In addition, we quantified and compared the interspecies differences in expression of the hepatobiliary transporters, corresponding to the above human transporters, in liver tissue and hepatocytes of male beagle dogs, cynomolgus monkeys, SpragueDawley rats, and Wistar rats. In all the species, the sinusoidal OATPs/ Oatps were the most abundant hepatic transporters. However, there were notable interspecies differences in the relative abundance of the remaining transporters. For example, the next most abundant transporter in humans and monkeys was OCT1/Oct1, whereas it was Mrp2 and Ntcp in dogs/Wistar rats and Sprague-Dawley rats, respectively. In contrast, the protein expression of the efflux transporters BCRP/Bcrp, MDR1/Mdr1, MRP3/Mrp3, MRP4/Mrp4, and MATE1/Mate1 was much lower across all the species. For most transporters, the expression in the liver tissues was comparable to that in the unplated cryopreserved hepatocytes. These data on human liver transporter protein expression complete the picture of the expression of major human hepatobiliary transporters important in drug disposition and toxicity. In addition, the data on expression of the corresponding hepatobiliary transporters in preclinical species will be helpful in interpreting and extrapolating pharmacokinetic, pharmacological, and toxicological results from preclinical studies to humans.

Evaluation of Rosuvastatin as an Organic Anion Transporting Polypeptide (OATP) Probe Substrate: In Vitro Transport and In Vivo Disposition in Cynomolgus Monkeys

“…The contribution of both OATPs represents 70% of total hepatic active uptake; the remaining active uptake (30%) is attributed to NTCP (Ho et al, 2006;Kitamura et al, 2008;Bi et al, 2013). Consistent with the contribution of individual transporters to the overall hepatic uptake of RSV, OATPs and NTCP comprise two of the most abundant sinusoidal uptake transporters in human liver tissues, with relative abundance of quantifiable hepatic transporters of 29% and 13%, respectively, when quantified transporter protein expression in a human liver bank (n 5 55) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (Wang et al, 2015). Furthermore, for most transporters, the expression in the liver tissues was comparable to that in the cryopreserved hepatocytes (Wang et al, 2015).…”

“…Consistent with the contribution of individual transporters to the overall hepatic uptake of RSV, OATPs and NTCP comprise two of the most abundant sinusoidal uptake transporters in human liver tissues, with relative abundance of quantifiable hepatic transporters of 29% and 13%, respectively, when quantified transporter protein expression in a human liver bank (n 5 55) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (Wang et al, 2015). Furthermore, for most transporters, the expression in the liver tissues was comparable to that in the cryopreserved hepatocytes (Wang et al, 2015). In addition to in vitro assessment, RSV has often been used for kinetic studies in vivo in several species, including humans Simonson et al, 2004;Prueksaritanont et al, 2014), monkeys (Shen et al, 2013), mice (Salphati et al, 2014), rats (Wen and Xiong, 2011), and pigs (Bergman et al, 2009).…”

Evaluation of Cynomolgus Monkeys for the Identification of Endogenous Biomarkers for Hepatic Transporter Inhibition and as a Translatable Model to Predict Pharmacokinetic Interactions with Statins in Humans

“…Cynomolgus monkey cOATP1B1 and cOATP1B3, however, show a high degree of amino acid sequence identity with human orthologs (Shen et al, 2013) but higher hepatic protein amounts as compared with humans (Wang et al, 2015). Both cOATP1B1 and cOATP1B3 are functionally similar to their human orthologs, both in terms of in vitro transport activity and inhibition potency with selected substrates and inhibitors tested (Shen et al, 2013).…”

Proteomic Analysis of the Developmental Trajectory of Human Hepatic Membrane Transporter Proteins in the First Three Months of Life

“…For example, hepatic mRNA expression of mouse Oatps gradually increases after birth until adult levels at 6 wk of age (Cheng et al, 2005). In spite of the maturation in animal studies, interspecies differences prevent us from translating animal maturation data to humans (Wang et al, 2015). For humans, only few transporters have been studied, and two recent reviews showed that a clear information gap remains on the developmental trajectory of individual transporters in fetuses and young children and the related impact on drug disposition (Brouwer et al, 2015;Mooij et al, 2015).…”