Cholestasis is impaired secretion of bile. As it results in a multitude of toxins building up and has been difficult to treat it has been of perhaps as much interest to pharmacologists as gastroenterologists.
Bile Acid homeostasis
Primary bile acids are created from cholesterol by cholesterol 7α-hydroxylase CYP7A1 and then sterol 12α-hydrolyase CYP8B1 in bile acid biosynthesis. Bile acid transporters then secrete them into the intestine. The Bile acid transporters are:
- Bile-salt excretory pump (BSEP)
- Multidrug-resistance-associated protein 2(MRP2)
- Multidrug-resistance-associated protein 3(MRP3)
Secondary bile acids are then formed by bacteria which contain enzymes which undertake 7α-hydroxylation of the primary bile acids, and these are then absorbed into the blood. Hepatocytes extract these with an active uptake mechanism using Na+-taurochlorate-cotransporting polypeptide(NTCP) and Na+-independent organic anion-transporting polypeptide 2(DATP2). These then circulate between the hepatocyte, gut and blood.
- Oestrogens and tamoxifen
- Erythromycin and other macrolides
- Co-amoxiclav, flucloxacillin and other oxypenicillins
- Bile acids themselves are toxic
- Rifampicin in patients intolerant to colestyramine.
- Ursodeoxycholic acid
- Possibly fanesol X receptor activators
- Chenodexycholic acid and some other bile acids (less strongly)
- ? 6-α-ethylchenodeoxycholic acid (6ECDCA)(potent-investigational)
- Possibly Pregnane X receptor activators