by Ed Barillas, Staff Writer
In Part 1, we looked at how 17-glucuronides are the cause for liver toxicity. We shall now look upon how they cause cholestasis. First off, bile is passed in two ways, as bile salt dependent flow and bile salt independent flow. An uninvolved process controlled chiefly by the osmotic factors bicarbonate and glutathione is called bile salt independent flow. What actually happens is not common knowledge other that the biliary glutathione levels decrease dramatically soon after a toxic steroid is taken and then total hepatic glutathione increases which shows that glutathione transport to the bile duct becomes impaired. Bicarbonate passage to the bile is likewise impaired but it is not due to impaired transporters, but rather the gradient lessened by a type of bicarbonate reuptake. These happen swiftly and are the primary toxicities seen.
Bile salt dependent flow is an active process controlled by many membrane bound transporters. Mainly bind cassette transporters transport the bile salts from the blood and through the hepatocyte and then on to hepatocyte and to the bile. The pumping action of bile salts that go into the bile force that drives bile flow is what is supposed to occur for normal functioning.
It is said that canilicular and basolateral transporters are probably involved in hormone-induced cholestasis. The one most looked at is canilicular bile salt export pump. Also, oral steroid glucuronides have been known to intermingle with the promoter region of the gene for this transporter and to repress its expression. Aside from repression of the gene, there are many other things that may lessen the BSEP function as well. The transport of the BSEP from its point of synthesis by way of the canilicular membrane can be impaired in cholestasis supporting functional transporters in the wrong area of the cell.
In conclusion, you must look at the genetic component. There are various genetic variations in ABC transporter in the population. Some people are at a much higher risk for developing cholestasis than others and some say that in the future it will be possible for people to conclude what genetic polymorphisms they have in their hepatic transporters. One must take into account this valuable information if you are planning to take a potentially liver toxic drug. Meanwhile, the choice method for determining if one is at risk for cholestatic perils is to look into your own family. Some conditions to look out for include, Dubin-Johnson syndrome, pregnancy, progressive familial intrahepatic cholestasis and benign recurrent intrahepatic cholestasis. The closer the relative is to you, the higher the odds of having toxicity issues with oral AAS.