Association Study of SLCO1B3 and ABCC3 Genetic Variants in Gallstone Disease

Banach, Bolesław; Modrzejewski, Andrzej; Juzyszyn, Zygmunt; Kurzawski, Mateusz; Sroczyński, Tomasz; Pawlik, Andrzej

doi:10.3390/genes13030512

Cited by 3 publications

(2 citation statements)

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“…Therefore, the findings of this study predicted that inhibitor of UGT1A1 might be helpful for NAFLD/NASH treatment. As the bile acid pathway mediated genes, ABCC3 played a central role in bile acid transporter and NPC1 maintained cholesterol homeostasis (Banach et al, 2022;Lu, 2022). The mRNA levels of both ABCC3 and NPC1 were reduced in the liver tissues of mice fed with HFD.…”

Section: Discussionmentioning

confidence: 99%

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

Jia

et al. 2023

Front. Pharmacol.

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Introduction: The pathological progression of non-alcoholic fatty liver disease (NAFLD) is driven by multiple factors, and non-alcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/ NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding.Methods: A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. Data are available via Proteome X change with identifier PXD040233. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data.Results: Bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and GSTA1). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP3A11 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3).Discussion: These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

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Section: Discussionmentioning

confidence: 99%

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

Jia

et al. 2023

Front. Pharmacol.

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“…These ABC proteins transport various molecules across extra- and intracellular membranes. The specific function of this transporter has not yet been determined; however, it was reported to mediate biliary and intestinal excretion of organic anions ( Banach et al, 2022 ). The functional activity of some ABCC3 variants has been fully examined ( Singh et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Exploratory focused pharmacogenetic testing reveals novel markers associated with risperidone pharmacokinetics in Saudi children with autism

Shilbayeh,

Adeen,

Ghanem

et al. 2024

Front. Pharmacol.

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Background: Autism spectrum disorders (ASDs) encompass a broad range of phenotypes characterized by diverse neurological alterations. Genomic studies have revealed considerable overlap between the molecular mechanisms implicated in the etiology of ASD and genes involved in the pharmacokinetic (PK) and pharmacodynamic (PD) pathways of antipsychotic drugs employed in ASD management. Given the conflicting data originating from candidate PK or PD gene association studies in diverse ethnogeographic ASD populations, dosage individualization based on “actionable” pharmacogenetic (PGx) markers has limited application in clinical practice. Additionally, off-label use of different antipsychotics is an ongoing practice, which is justified given the shortage of approved cures, despite the lack of satisfactory evidence for its safety according to precision medicine. This exploratory study aimed to identify PGx markers predictive of risperidone (RIS) exposure in autistic Saudi children.Methods: This prospective cohort study enrolled 89 Saudi children with ASD treated with RIS-based antipsychotic therapy. Plasma levels of RIS and 9-OH-RIS were measured using a liquid chromatography–tandem mass spectrometry system. To enable focused exploratory testing, genotyping was performed with the Axiom PharmacoFocus Array, which included a collection of probe sets targeting PK/PD genes. A total of 720 PGx markers were included in the association analysis.Results: A total of 27 PGx variants were found to have a prominent impact on various RIS PK parameters; most were not located within the genes involved in the classical RIS PK pathway. Specifically, 8 markers in 7 genes were identified as the PGx markers with the strongest impact on RIS levels (p < 0.01). Four PGx variants in 3 genes were strongly associated with 9-OH-RIS levels, while 5 markers in 5 different genes explained the interindividual variability in the total active moiety. Notably, 6 CYP2D6 variants exhibited strong linkage disequilibrium; however, they significantly influenced only the metabolic ratio and had no considerable effects on the individual estimates of RIS, 9-OH-RIS, or the total active moiety. After correction for multiple testing, rs78998153 in UGT2B17 (which is highly expressed in the brain) remained the most significant PGx marker positively adjusting the metabolic ratio. For the first time, certain human leukocyte antigen (HLA) markers were found to enhance various RIS exposure parameters, which reinforces the gut–brain axis theory of ASD etiology and its suggested inflammatory impacts on drug bioavailability through modulation of the brain, gastrointestinal tract and/or hepatic expression of metabolizing enzymes and transporters.Conclusion: Our hypothesis-generating approach identified a broad spectrum of PGx markers that interactively influence RIS exposure in ASD children, which indicated the need for further validation in population PK modeling studies to define polygenic scores for antipsychotic efficacy and safety, which could facilitate personalized therapeutic decision-making in this complex neurodevelopmental condition.

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