Steroid D-ring glucuronides: characterization of a new class of cholestatic agents.

In summary, we have shown that steroid D-ring, but not steroid A-ring, glucuronide conjugates act at the level of the bile canaliculus to decrease bile-acid-dependent flow, initially; and subsequently, bile-acid-independent flow. These data indicate that glucuronide conjugates are not necessarily inactive; the present glucuronides clearly possess toxicological activity. The cholestatic glucuronides are all natural, endogenously formed products of metabolism. The critical questions which remain are whether metabolism of steroids to D-ring glucuronides is an obligatory step in the etiology of steroid-induced cholestasis and whether these glucuronides, at concentrations attained in humans, are capable of decreasing hepatic excretory function and inducing morphological and biochemical changes of clinical importance.