A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus

Abstract

A single nucleotide polymorphism characterized by the substitution of valine for glutamate (V1188E) in exon 25 of the multidrug resistance protein 2 gene was found in a group of patients with primary biliary cirrhosis. This heterozygous mutation was significantly associated with the presence of pruritus. (HEPATOLOGY 2006;43:1152-1154

Hepatic expression of endocannabinoid receptors and their novel polymorphisms in primary biliary cirrhosis

“…The SNP of the CB1 and CB2 receptor genes identified in this study was not associated with the presence or absence of pruritus or with fatigue, in contrast to the other genetic SNP data previously published [15,16].…”

“…In addition, the use of a cannabinoid receptor agonist, dronabinol, was reported to relieve intractable pruritus in a small group of patients with cholestasis [14]; as CB1 is expressed in sensory nerves, which are involved in the transmission of sensory input (e.g., pruritus), and as receptor polymorphisms in other genes [15,16] have been found in patients with PBC who do or do not report itch, there is a rationale for exploring the presence of CB1 and CB2 polymorphisms in the context of symptoms in these patients.…”

Pruritus

“…In this context, however, some transporters that can transport opiates in vitro are common to the basolateral domain of the hepatocyte, to the choroid plexus, and to the blood-brain barrier [11]. Accordingly, it is plausible that they can also transport peripheryderived opioids into the CNS, which would increase central opioidergic tone.…”

“…In addition, ethnicity may inform the experience of side effects, including pruritus, from the administration of intravenous morphine in children [29]. Thus, SNP in the gene that codes OPRM1 may also explain, in part, why not all patients with cholestasis report pruritus (see above) [8,11]. Accordingly, genetic analyses that apply techniques including genome-wide association studies may be useful in identifying specific features in the group of genes that code for transport proteins in the hepatobiliary system, in the CNS, and those involved in the activation of sensory neurons including the phospholipase C B3 pathway [30].…”

“…In the hepatocyte, MRP2 (ABCC2) mediates the transport of several organic anions [11] and, interestingly, in the context of the pruritus of cholestasis, opioid ligands are substrates of MRP2 [11]. A single nucleotide polymorphism (SNP) characterized by the substitution of valine for glutamate (V1188E) in exon 25 of the MRP2 gene was found in heterozygosity in a group of patients with PBC [11], and significantly associated with the presence of pruritus. Thus, V1188E in MRP2 may change the way the pruritogen(s) or its cofactors are transported from the hepatocyte into the bile canalicula or into the central nervous system (CNS).…”