Selected ABCB1, ABCB4 and ABCC2 Polymorphisms Do Not Enhance the Risk of Drug-Induced Hepatotoxicity in a Spanish Cohort

Singh

J Biochem & Molecular Tox

2022

ATP‐binding cassette (ABC) transporters are expressed in various human tissues and play a vital role in the efflux of various chemotherapeutic drugs. The current study has assessed genetic variants of ABCB1, ABCC1, ABCC2, and ABCG2 genes in 407 lung cancer patients undergoing platinum‐based doublet chemotherapy. The association of ABCB1 (C1236T, C3435T, and G2677T/A), ABCC1 (G3173A and G2168A),ABCC2 (G4544A), and ABCG2 (C421A) polymorphisms with chemotherapy‐induced adverse events were assessed, and statistical analysis was conducted. Our data showed that patients harboring heterozygous (GA) genotype for ABCC1 G3173A had an increased risk of developing leukopenia (odds ratio [OR] = 1.88, p = 0.04) and anemia (adjusted odds ratio [AOR] = 2.70, p = 0.03). For ABCC2 G4544A polymorphism, patients harboring one copy of the mutant (GA) allele showed an increased risk of developing anemia (OR = 4.24, p = 0.03). After adjusting with various confounding factors, the heterozygous (GA) genotype showed a 5.63‐fold increased risk of developing anemia (AOR = 5.63, p = 0.03). The ABCB1 G2677A (OR = 0.37, p = 0.008) and ABCC1 G3173A (OR = 0.54, p = 0.04) polymorphism showed a lower incidence of developing nephrotoxicity. In ABCG2 C421A polymorphism, patients harboring heterozygous (CA) genotype had a lower incidence of having diarrhea (OR = 0.25, p = 0.04). An increased risk of having diarrhea was observed in the heterozygous genotype (GA) for ABCC1 G3173A polymorphism (AOR = 2.78, p = 0.04). An increased risk of liver injury was found in the patients carrying heterozygous genotype of the ABCC1 G3173A (OR = 2.06, p = 0.02) and ABCB1 C1236T (OR = 1.85, p = 0.01). This study demonstrates the role of polymorphic variations in ABCB1, ABCC1, ABCC2, and ABCG2 in predicting hematological, nephrotoxicity, gastrointestinal, and hepatotoxicity.

Section: Discussionmentioning

confidence: 66%

Genetic variations in ABC transporter genes as a predictive biomarker for toxicity in North Indian lung cancer patients undergoing platinum‐based doublet chemotherapy

Singh

J Biochem & Molecular Tox

2022

“…Further work from this group using the Spanish DILI Registry, performed extended genetic sequencing for common variants in ABCB1 , ABCB4 and ABCC2 , in 141 patients with DILI and compared these to healthy controls. Results detected no significant difference in common variants for these genes between the groups 23 …”

Section: Drug‐induced Liver Injurymentioning

confidence: 74%

Review article: liver disease in adults with variants in the cholestasis‐related genes ABCB11, ABCB4 and ATP8B1

Nayagam

Williamson

Joshi

et al. 2020

Aliment Pharmacol Ther

SummaryBackgroundChildren with intrahepatic cholestasis and genetic variants which result in the disruption of the formation and maintenance of bile (ABCB11, ABCB4 and ATP8B1) generally have a rapidly progressive clinical course. Adults with different phenotypes of cholestasis are increasingly being evaluated for variants in these genes associated with childhood diseases.AimsTo review the literature with respect to the presence of variants in cholestasis‐related genes in adults with various liver phenotypes, and provide clinical implications of the findings.MethodsA search of the literature on variants in specific cholestasis‐related genes in adults was conducted.ResultsThe common variant p.Val444Ala in ABCB11 confers increased risk of drug‐induced liver injury and intrahepatic cholestasis of pregnancy (ICP). Individuals with variants in ABCB4 are at risk of ICP and low phospholipid‐associated cholelithiasis. Variants in ABCB4, and possibly ABCB11 and ATP8B1, can be identified in up to a third of patients with cryptogenic chronic cholestasis.ConclusionsIndividuals with variants in ABCB11 rarely develop cholestasis until BSEP function dips below a threshold, which is also affected by other factors (e.g., drugs, hormones). However, variants in ABCB4 and consequent reduction in MDR3 protein, have a more linear dose‐response curve. In individuals with an ABCB11 variant, medications known to reduce BSEP activity should be used cautiously; they should be monitored during pregnancy for ICP; and first‐degree relatives should be counselled and screened. No proven management strategy exists, although ursodeoxycholic acid may be beneficial. Further work is needed to define the genotype‐phenotype correlation and natural history, and to evaluate the penetrance.

“…In African populations, the single nucleotide polymorphism (SNP) of ABCB1 rs1045642 can greatly reduce the susceptibility to hepatotoxicity of nevirapine ( Ritchie et al, 2006 ), however, ABCB1 rs2032582 has taken the place of ABCB1 rs1045642 in Japanese patients ( Fukunaga et al, 2016 ). ABCC2 rs717620 mutation can cause the active metabolite of diclofenac to accumulate diclofenac acyl glucuronide in the liver, leading to hepatotoxicity ( Daly et al, 2007 ), but the Spanish population ( Ulzurrun et al, 2014 ) does not support the role of ABCB1 , ABCC2 and ABCB4 transporter gene polymorphisms in the occurrence and development of DILI.…”

Section: Dili and Gene Polymorphismmentioning

confidence: 99%

Research Progress of Pharmacogenomics in Drug-Induced Liver Injury

et al. 2021

Background: Drug-induced liver injury (DILI) is a common and serious adverse drug reaction with insufficient clinical diagnostic strategies and treatment methods. The only clinically well-received method is the Roussel UCLAF Causality Assessment Method scale, which can be applied to both individuals and prospective or retrospective studies. However, in severe cases, patients with DILI still would develop acute liver failure or even death. Pharmacogenomics, a powerful tool to achieve precision medicine, has been used to study the polymorphism of DILI related genes.Summary: We summarized the pathogenesis of DILI and findings on associated genes and variations with DILI, including but not limited to HLA genes, drug metabolizing enzymes, and transporters genes, and pointed out further fields for DILI related pharmacogenomics study to provide references for DILI clinical diagnosis and treatment.Key Messages: At present, most of the studies are mainly limited to CGS and GWAS, and there is still a long way to achieve clinical transformation. DNA methylation could be a new consideration, and ethnic differences and special populations also deserve attention.