SLCO1B1 *15 haplotype is associated with rifampin-induced liver injury

Abstract

Abstract. The organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) plays an important role in the transport of endogenous and xenobiotic compounds, such as bile acids and rifampin. In this study, the association between OATP1B1 polymorphisms and rifampin hepatotoxicity was investigated using integrated population genetic analysis and functional studies. A total of 273 unrelated patients treated with rifampin were recruited. The allele frequencies were examined in patients with drug (rifampin)-induced liver injury (DILI) (n=118) and without (non-DILI) (n=155). Functional analyses were conducted to determine whether the inhibition of bile acids by rifampin was associated with OATP1B1 variants. In the present study, 24 single nucleotide polymorphisms (SNPs) in OATP1B1 were detected in a Chinese population, with two of them causing an amino acid change (rs2306283 and rs4149056). The haplotypes constructed by these two SNPs were OATP1B1 IntroductionRifampin (RMP) is one of the major antituberculosis drugs, a second-choice antistaphylococcal agent and an effective medicine in controlling pruritus in primary biliary cirrhosis (1-3). The common adverse reactions to RMP include fever, nausea, vomiting, diarrhea, abdominal pain, hemolytic anemia, thrombocytopenia, liver injury and tubular defects. The hepatotoxicity induced by RMP was first reported in 1971, and it has an incidence rate of 5 to 12.5% (4,5). RMP-induced hepatotoxicity can be divided into three categories: hepatocellular, cholestatic or mixed-type injury (6). In spite of the well-accepted toxicity of RMP in vivo, its toxic mechanism remains unclear. Recently, one important mechanism was determined to be a rise in serum bilirubin via competitive inhibition of hepatocyte bilirubin transport by RMP (7). The inhibition of the hepatic uptake of bile acid has been proposed as the mechanism responsible for RMP-induced cholestasis (8). Notably, the genetic polymorphisms of bile acid transporters have been reported to be closely related to the susceptibility to RMP hepatotoxicity (9).Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) is one of the most important bile acid transporters. It is mainly expressed on the basolateral membrane of human hepatocytes and is responsible for bilirubin uptake (10,11). Several studies have demonstrated that OATP1B1 plays an important role in the hepatic uptake of RMP (12). In particular, it has displayed a great capability for RMP transport in HeLa cells, with RMP uptake being markedly decreased by the OATP1B1 allelic variants (13). To date, however, many studies of RMP hepatotoxicity have concentrated on the transporters that export RMP, and few studies have been published concerning the importance of the transporters that uptake RMP. In fact, RMP inhibits the uptake of bile acids by OATP1B1 (14). For example, RMP inhibits OATP1B1-mediated substrate uptake into the liver in a Xenopus laevis oocyte expression system (13

Microcystin-LR induced liver injury in mice and in primary human hepatocytes is caused by oncotic necrosis

“…While oral exposure has a higher acceptable margin of safety, the fact that exposure to concentrations of microcystin less than one order of magnitude higher than the current minimum standard of MC-LR can induce LDH release in hepatocytes indicates that current margins of safety should be re-evaluated. Recreational activity and incidental consumption of water with even only moderately elevated MC-LR could potentially lead to toxicity in vulnerable populations, including children, genetically predisposed populations with enhanced OATP1B1 activity (Li et al, 2012), and patients with ongoing liver disease. Given that patients rapidly proceed to ALF after acute MC-LR intoxication, exposure to even low levels could result in unacceptably high morbidity and mortality rates in the event of civilian exposure to a contaminated water source, especially given the likelihood that multiple microcystin species are commonly present in water simultaneously.…”

Genomewide Association Study Confirming the Association of NAT2 with Susceptibility to Antituberculosis Drug-Induced Liver Injury in Thai Patients

“…In general, the development of DILI is associated with several important risk factors, such as advanced age, gender, malnutrition, complications of disease, alcohol intake, and genetic factors (11). In addition, many candidate gene studies reported associations between ATDILI and N-acetyltransferase 2 (NAT2) (11)(12)(13), cytochrome P450 2E1 (CYP2E1) (14), glutathione S-transferase M1 (GSTM1) (15), glutathione S-transferase T1 (GSTT1) (16), superoxide dismutase 1 (SOD1) (17), HLA-DQA1/DQB1 (18), and the solute carrier organic anion transporter family member 1B1 (SLCO1B1) (19).…”

Influence of genetic variants on toxicity to anti-tubercular agents: a systematic review and meta-analysis (protocol)

“…Rifampicin and pyrazinamide have also been reported to be hepatotoxic [29, 30]; however, the mechanisms for rifampicin-induced hepatotoxicity and pyrazinamide-induced hepatotoxicity are unknown and unpredictable [4]. Some speculated genetic variants, such as SLCO1B1 , have been linked to toxicity with rifampicin, although limited data are available to support this claim [29].…”

“…Some speculated genetic variants, such as SLCO1B1 , have been linked to toxicity with rifampicin, although limited data are available to support this claim [29]. No hepatotoxicity has been described for ethambutol.…”