Real-world pharmacogenetics of statin intolerance: effects of SLCO1B1, ABCG2, and CYP2C9 variants

Lönnberg, K. Ivar; Tornio, Aleksi; Hirvensalo, Päivi; Keskitalo, Jenni E.; Mustaniemi, Anna-Liina; Kiiski, Johanna I.; Filppula, Anne M.; Niemi, Mikko

doi:10.1097/fpc.0000000000000504

Cited by 4 publications

(2 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fluvastatin and rosuvastatin also inhibited the hypercapnia-induced increase in cholesterol in lipid rafts in VERO ( Figure 4H ) and in BEAS-2B ( Supplementary Figure 6A ) cells. Of note, uptake of statins into cells is mediated by organic anion transporting polypeptide (OATP)1B1 (encoded by SLCO1B1 ), while efflux of statins from cells is mediated by the breast cancer resistance protein (BCRP, encoded by ABCG2 ) ( 44 ). In previously published work, we confirmed that SLCO1B1 and ABCG2 are transcribed in HBE cells ( 18 ).…”

Section: Resultsmentioning

confidence: 99%

Hypercapnia increases ACE2 expression and pseudo-SARS-CoV-2 entry in bronchial epithelial cells by augmenting cellular cholesterol

Chen,

Matsuda,

Budinger

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

Patients with chronic lung disease, obesity, and other co-morbid conditions are at increased risk of severe illness and death when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hypercapnia, the elevation of CO2 in blood and tissue, commonly occurs in patients with severe acute and chronic lung disease, including those with pulmonary infections, and is also associated with high mortality risk. We previously reported that hypercapnia increases viral replication and mortality of influenza A virus infection in mice. We have also shown that culture in elevated CO2 upregulates expression of cholesterol synthesis genes in primary human bronchial epithelial cells. Interestingly, factors that increase the cholesterol content of lipid rafts and lipid droplets, platforms for viral entry and assembly, enhance SARS-CoV-2 infection. In the current study, we investigated the effects of hypercapnia on ACE2 expression and entry of SARS-CoV-2 pseudovirus (p-SARS-CoV-2) into airway epithelial cells. We found that hypercapnia increased ACE2 expression and p-SARS-CoV-2 uptake by airway epithelium in mice, and in cultured VERO and human bronchial epithelial cells. Hypercapnia also increased total cellular and lipid raft-associated cholesterol in epithelial cells. Moreover, reducing cholesterol synthesis with inhibitors of sterol regulatory element binding protein 2 (SREBP2) or statins, and depletion of cellular cholesterol, each blocked the hypercapnia-induced increases in ACE2 expression and p-SARS-CoV-2 entry into epithelial cells. Cigarette smoke extract (CSE) also increased ACE2 expression, p-SARS-CoV-2 entry and cholesterol accumulation in epithelial cells, an effect not additive to that of hypercapnia, but also inhibited by statins. These findings reveal a mechanism that may account, in part, for poor clinical outcomes of SARS-CoV-2 infection in patients with advanced lung disease and hypercapnia, and in those who smoke cigarettes. Further, our results suggest the possibility that cholesterol-lowering therapies may be of particular benefit in patients with hypercapnia when exposed to or infected with SARS-CoV-2.

show abstract

Section: Resultsmentioning

confidence: 99%

Hypercapnia increases ACE2 expression and pseudo-SARS-CoV-2 entry in bronchial epithelial cells by augmenting cellular cholesterol

Chen,

Matsuda,

Budinger

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…1,[3][4][5][6][7][8] This increases the risk of statin-associated musculoskeletal symptoms. [8][9][10] Furthermore, increased function SLCO1B1 alleles have been associated with decreased plasma concentrations of OATP1B1 substrate drugs, such as rosuvastatin, simvastatin acid, and methotrexate. 6,7,11 Moreover, inhibition of OATP1B1 can impair the hepatic uptake of OATP1B1 substrates and increase their plasma concentrations.…”

Section: Introductionmentioning

confidence: 99%

Non‐targeted metabolomics for the identification of plasma metabolites associated with organic anion transporting polypeptide 1B1 function

Hämäläinen,

Hirvensalo,

Neuvonen

et al. 2024

Clinical Translational Sci

Self Cite

View full text Add to dashboard Cite

Our aim was to evaluate biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) function using a hypothesis‐free metabolomics approach. We analyzed fasting plasma samples from 356 healthy volunteers using non‐targeted metabolite profiling by liquid chromatography high‐resolution mass spectrometry. Based on SLCO1B1 genotypes, we stratified the volunteers to poor, decreased, normal, increased, and highly increased OATP1B1 function groups. Linear regression analysis, and random forest (RF) and gradient boosted decision tree (GBDT) regressors were used to investigate associations of plasma metabolite features with OATP1B1 function. Of the 9152 molecular features found, 39 associated with OATP1B1 function either in the linear regression analysis (p < 10−5) or the RF or GBDT regressors (Gini impurity decrease > 0.01). Linear regression analysis showed the strongest associations with two features identified as glycodeoxycholate 3‐O‐glucuronide (GDCA‐3G; p = 1.2 × 10−20 for negative and p = 1.7 × 10−19 for positive electrospray ionization) and one identified as glycochenodeoxycholate 3‐O‐glucuronide (GCDCA‐3G; p = 2.7 × 10−16). In both the RF and GBDT models, the GCDCA‐3G feature showed the strongest association with OATP1B1 function, with Gini impurity decreases of 0.40 and 0.17. In RF, this was followed by one GDCA‐3G feature, an unidentified feature with a molecular weight of 809.3521, and the second GDCA‐3G feature. In GBDT, the second and third strongest associations were observed with the GDCA‐3G features. Of the other associated features, we identified with confidence two representing lysophosphatidylethanolamine 22:5. In addition, one feature was putatively identified as pregnanolone sulfate and one as pregnenolone sulfate. These results confirm GCDCA‐3G and GDCA‐3G as robust OATP1B1 biomarkers in human plasma.

show abstract

Understanding the impact of ABCG2 polymorphisms on drug pharmacokinetics: focus on rosuvastatin and allopurinol

Kasten,

Cascorbi

2024

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

Real-world pharmacogenetics of statin intolerance: effects of SLCO1B1, ABCG2, and CYP2C9 variants

Cited by 4 publications

References 39 publications

Hypercapnia increases ACE2 expression and pseudo-SARS-CoV-2 entry in bronchial epithelial cells by augmenting cellular cholesterol

Hypercapnia increases ACE2 expression and pseudo-SARS-CoV-2 entry in bronchial epithelial cells by augmenting cellular cholesterol

Non‐targeted metabolomics for the identification of plasma metabolites associated with organic anion transporting polypeptide 1B1 function

Understanding the impact of ABCG2 polymorphisms on drug pharmacokinetics: focus on rosuvastatin and allopurinol

Contact Info

Product

Resources

About