Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis
Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis...
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/6/5823 |
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| author | Giovanni Vitale Alessandro Mattiaccio Amalia Conti Sonia Berardi Vittoria Vero Laura Turco Marco Seri Maria Cristina Morelli |
| author_facet | Giovanni Vitale Alessandro Mattiaccio Amalia Conti Sonia Berardi Vittoria Vero Laura Turco Marco Seri Maria Cristina Morelli |
| author_sort | Giovanni Vitale |
| collection | DOAJ |
| description | Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver’s metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (<i>ABCB11</i>); 2. the multidrug resistance protein-2 (MRP2, <i>ABCC2</i>) regulating the bile salts’ independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, <i>ABCB1</i>) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, <i>ABCB4</i>). Two of the most known proteins involved in bile acids’ (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs’ secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the <i>ABCB4</i> gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs. |
| first_indexed | 2024-03-11T06:25:38Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T06:25:38Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f5f6fe4c4d21491aacf2b567a1dac4772023-11-17T11:39:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01246582310.3390/ijms24065823Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic CholestasisGiovanni Vitale0Alessandro Mattiaccio1Amalia Conti2Sonia Berardi3Vittoria Vero4Laura Turco5Marco Seri6Maria Cristina Morelli7Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyU.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyU.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyInternal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyInternal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyInternal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyU.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyInternal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyIdiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver’s metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (<i>ABCB11</i>); 2. the multidrug resistance protein-2 (MRP2, <i>ABCC2</i>) regulating the bile salts’ independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, <i>ABCB1</i>) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, <i>ABCB4</i>). Two of the most known proteins involved in bile acids’ (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs’ secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the <i>ABCB4</i> gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs.https://www.mdpi.com/1422-0067/24/6/5823drug-induced cholestasisidiosyncratic drug-induced liver injuryMDR1 proteinMRP2BSEP proteinMDR3 protein |
| spellingShingle | Giovanni Vitale Alessandro Mattiaccio Amalia Conti Sonia Berardi Vittoria Vero Laura Turco Marco Seri Maria Cristina Morelli Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis International Journal of Molecular Sciences drug-induced cholestasis idiosyncratic drug-induced liver injury MDR1 protein MRP2 BSEP protein MDR3 protein |
| title | Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis |
| title_full | Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis |
| title_fullStr | Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis |
| title_full_unstemmed | Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis |
| title_short | Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis |
| title_sort | molecular and clinical links between drug induced cholestasis and familial intrahepatic cholestasis |
| topic | drug-induced cholestasis idiosyncratic drug-induced liver injury MDR1 protein MRP2 BSEP protein MDR3 protein |
| url | https://www.mdpi.com/1422-0067/24/6/5823 |
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