Effect of drug transporter pharmacogenetics on cholestasis

Abstract

Polymorphisms in transporter genes are frequent. For clinically relevant cholestatic syndromes, it often requires a combination of genetic variants or acquired triggers such as pregnancy or drug treatment. In combination with other pathogenetic aspects, genetic variants in drug transporters may contribute to our understanding of not only cholestatic diseases such as primary sclerosing cholangitis or primary biliary cirrhosis, but also the natural course of chronic liver disease in general.

Clinical Applicability of Whole-Exome Sequencing Exemplified by a Study in Young Adults with the Advanced Cryptogenic Cholestatic Liver Diseases

“…Other polymorphisms, especially in the ABCB11 and ABCB4 genes, are usually clinically harmless [38]. Their clinically relevant cholestatic syndromes, similar to those related to the V444A polymorphism of BSEP, are in combination with acquired triggers such as pregnancy or exposure to drugs or toxins [3, 39, 40]. Various other forms of hereditary cholestasis (such as Aagenaes syndrome, North American Indian childhood cirrhosis, cirhin deficiency, Dubin-Johnson syndrome, and Alagille syndrome) may result from rare mutations of genes encoding bile acid synthesis enzymes ( CYP7A1 [26], CYP7B1 [27], HSD3B7 [28], and AKR1D1 [29]), the bile acid receptor farnesoid X receptor (FXR), the Notch signaling pathway, sodium taurocholate cotransporting polypeptide (NTCP), or tight junction proteins along the canalicular membrane of hepatocytes and cholangiocytes [2, 4, 5].…”

“…Various other forms of hereditary cholestasis (such as Aagenaes syndrome, North American Indian childhood cirrhosis, cirhin deficiency, Dubin-Johnson syndrome, and Alagille syndrome) may result from rare mutations of genes encoding bile acid synthesis enzymes ( CYP7A1 [26], CYP7B1 [27], HSD3B7 [28], and AKR1D1 [29]), the bile acid receptor farnesoid X receptor (FXR), the Notch signaling pathway, sodium taurocholate cotransporting polypeptide (NTCP), or tight junction proteins along the canalicular membrane of hepatocytes and cholangiocytes [2, 4, 5]. In turn, drug-induced liver injury is the most commonly acquired cholestatic disease in adults [3]. In some cases the acute form of drug-induced liver injury may progress to chronic liver disease [41].…”

“…Moreover, this patient possessed another deleterious variant: PEMT p.Arg226Trp which could predispose to the development of liver disease in the early years of life. Four patients (numbers 1, 2, 3, and 6) possessed a common polymorphism ABCB11 p.Ala444Val (three of them were homozygous for this variant), which in pregnant women or after exposure to hepatotoxic drugs or toxins may associate with intrahepatic cholestasis of pregnancy [31, 32] and other cholestatic syndromes [3, 39, 40]. Patient number 6 also possessed another located on this same gene.…”

“…Some hepatobiliary disorders are of strict genetic origin but the majority are more complex and arise from environmental exposure underlined by individual susceptibility. Such complex pathogenesis is frequently observed in cholestatic liver diseases (CLD), in which the risk of liver injury and its clinical presentation depends upon deteriorated hepatic excretion and enterohepatic circulation of bile acids and other cholephiles, directed by alterations in hepatocyte transporters or their transactivators [1–3]. However, there are still patients in whom liver injury must be termed as cryptogenic despite substantial diagnostic efforts.…”

Recent Advances in Application of Pharmacogenomics for Biotherapeutics

“…Furthermore, variations affecting therapeutic outcomes of these drugs are in genes required for their absorption, distribution, metabolism, or excretion. Thus, most of the early targets of this search for variations for Phase I enzymes (32)(33)(34)(35) or Phase II enzymes (36,37) transporters (36,(38)(39)(40)(41)(42)(43)(44) and receptors (45-53). However, there is a small but significant number of examples of application of PGx to BTs (Table II).…”