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BSEP inhibited induced cholestasis and its rescue mechanisms

Leeuwen, L. van (2017) BSEP inhibited induced cholestasis and its rescue mechanisms. Bachelor's Thesis, Biology.

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Cholestasis is a complicated, often drug-induced disease that can be triggered by inhibition of the Bile Salt Export Pump (BSEP) transporter. Often used drugs like birth control pills are due to their estrogen rich compounds the instigator in this problem. The present literature study is focused on drug-induced cholestasis caused by inhibition of BSEP. Possible rescue mechanisms, in this case other efflux transporters, will be evaluated on their ability to prevent drug-induced cholestasis. BSEP is the biggest transporter of amidated bile acids and stimulates bile acid dependent bile flow. When BSEP is inhibited, the amidated bile acid transport is shut down. The transport can be taken over by MRP2 or BCRP on the canalicular membrane, or by MRP1, MRP3, MRP4 or OST/ on the sinusoidal membrane. For the decrease in hepatotoxicity, MRP4 or OST/ seems to be a good option. Both have an amidated substrate specificity and are upregulated in case of cholestasis. This however will result in a movement of the toxic environment from the hepatocyte to elsewhere in the body. Concluding that these two transporters despite their lowering of the toxic state in the liver, can not restore the bile flow and can therefore not prevent from intrahepatic cholestasis. To maintain a proper bile flow, the BCRP transporter on the canalicular membrane is important. The BCRP transporter has transport activity for both the amidated- and conjugated- form of bile acids. BCRP is the only option for the transport of amidated bile acids into the bile ducts to restore bile flow. Due to its low distribution of this transporter in the liver it is not able to completely take over BSEP function. For the same reason, BCRP is not able to prevent from intrahepatic cholestasis. However, if in the future 17-estradiol induced BCRP overexpression in the hepatocyte shows to be effective, this could be part of a a rescue mechanism for intrahepatic cholestasis. Besides the bile acid transporters there are also other factors of interest, named molecular interactions. These molecular interactions can induce cholestasis, and therefore should too be treated against.

Item Type: Thesis (Bachelor's Thesis)
Degree programme: Biology
Thesis type: Bachelor's Thesis
Language: English
Date Deposited: 15 Feb 2018 08:27
Last Modified: 15 Feb 2018 08:27

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