Complicity between Dual Inhibitors of BSEP and Mitochondrial Function

4 Complicity between Dual Inhibitors of BSEP and Mitochondrial Function 

Beyond individual considerations of the involvanent of certain hepatic transporters, like BSEP, and mitochondrial dysfunction on DILI, it is important to consider why these two risk factors can contribute so much to the manifestation of severe DILI in humans (Aleo et al., 2014). Bile acids, in general, appear to represent a more reliable marker of hepatic dysfunction regarding excretory abnormalities than serum bilirubin. Elevations in total bile acids can precede evidence of liver damage (as diagnosed by serum transaminase and bilirubin elevations) caused by hepatotoxic drugs by upward of 1 week (Fattinger et al., 2001). In order to explain this association, it is important to understand the intricate interactions between mitochondrial bioenergetics and transporter function within the liver. 

Subsequently, others (Kamiike et al., 1985) showed an exquisite time-course and functional dynamic fink between liver ATP content and bile flow in the rat under ischemic conditions and after ethionine and cyanide administration (see Fig. 8.3). 

An association between pharmacenticals that canse severe forms of DILI and dual inhibition of both BSEP and mitochondrial lespualion was reported recently (Aleoetal., 2014). 

FIGURE 8.3 Suppression of bile excretion and the ATP level in liver ischemia and their recoveries during recirculation. (O) = bile flow rate ( ) cellular level of ATP in the rat liver. Original work reproduced from Kamiike et al. (1985) with kind permission from Wolters Kluwer Health. 

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