Reversal of 2,3,7,8-tetrachlorodibenzo- p-dioxin-induced depression of ouabain biliary excretion by pregnenolone-16α-carbonitrile and spironolactone in isolated perfused rat livers

Abstract

Perfusate disappearance and biliary excretion of ouabain were depressed in isolated perfused livers of adult male rats 10 days after treatment with a single oral dose of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, 25 μg/kg). When TCDD-treated rats were given pregnenolone-16α-carbonitrile (PCN, 75 mg/kg/day) or spironolactone (S, 75 mg/kg/day) on Days 6–9, the depression in ouabain perfusate disappearance and biliary excretion on Day 10 was reversed, but the degree of reversal afforded by PCN was greater than S. Liver surface membrane (LSM) Mg 2+ ATPase and Na +, K + ATPase activity were also depressed 10 days after TCDD treatment and when TCDD-treated rats were given S on Days 6–9 the depression in both ATPase activities was completely reversed but treatment with PCN was less effective. Liver excretory function for ouabain and LSM Na +, K +, or Mg 2+ ATPase activity in control and TCDD-treated rats were altered independently by PCN and S treatment. Adrenalectomy on Day 6 after TCDD treatment did not reverse the depressant effects of TCDD on ouabain disposition but did prevent the increase in liver weight observed on Day 10. In view of the dissociation between hepatic excretory function for ouabain and LSM ATPase activities it is suggested that LSM Mg 2+ ATPase and Na +, K + ATPase are not directly involved in hepatic ouabain transport. We postulate that a LSM ouabain carrier unit, separate and distinct from these ATPases, is responsible for hepatic uptake and biliary excretion of ouabain.