harmine and Cholestasis

Harmol, a phenolic compound of low molecular weight, is conjugated either with glucuronic acid or sulfate. A clear relationship is observed between the metabolism of harmol and the occurrence of cholestasis: high concentrations of harmol glucuronide in bile induced a complete stop of bile flow, both in the rat in vivo and in the perfused rat liver. Intravenous infusion of harmol (250 mumol/hr/kg b.wt.) in vivo in the rat considerably decreased the availability of sulfate and, consequently, the amount of harmol sulfate excreted in bile and urine; this decrease was compensated for by an increase in glucuronidation, which caused complete cholestasis when the concentration of harmol glucuronide in bile became of the order of 20 mM. A sufficient supply of sulfate by infusion of sodium sulfate prevented the decrease in sulfation and the increase in glucuronidation and no cholestasis occurred. Low sulfate availability in rats fed a low-protein diet decreased the time of harmol infusion required for cholestasis to occur. Alleviation of the cholestasis in low-protein diet-fed rats was observed when after 2 hr of infusion of harmol additional sulfate was supplied. In the single-pass perfused rat liver, cholestasis occurred when large amounts of harmol glucuronide were excreted in bile. When sulfation of harmol was inhibited by 2,6-dichloro-4-nitrophenol, cholestasis occurred at lower infusion rates of harmol. These data indicate that harmol glucuronide is cholestatic when its concentration in bile increases beyond a threshold concentration; the protein content of the diet may profoundly affect the occurrence of this toxic effect.

Topics: Alkaloids; Animals; Cholestasis; Diet; Glucuronates; Harmine; Liver; Male; Rats; Rats, Inbred Strains; Sulfates; Time Factors

Harmol is conjugated by glucuronidation and sulfation when it is given to the rat in vivo. In the once-through perfused rat liver preparation glucuronidation of harmol shows kinetic aberrances [Pang et al., J. Pharmac. exp. Ther. 219, 134 (1981)]. In order to further delineate the mechanism behind this, sulfation was inhibited to about 10% of control by 2,6-dichloro-4-nitrophenol. The loss of sulfation was compensated by an increase in the rate of glucuronidation, keeping the total clearance by the liver virtually constant in spite of the loss of sulfation. The inhibition of sulfation eliminated the previously observed lag-phase in the kinetics of glucuronidation; the rate of glucuronidation was now almost linear with the input concentration of the substrate harmol. The constant clearance of harmol in spite of inhibition of sulfation, the occurrence of the lag-phase in glucuronidation in the presence of sulfation, and the disappearance of this lag-phase in the absence of sulfation can be explained by either diffusion-limited metabolism of harmol or a heterogeneous sub-lobular distribution of the sulfating and glucuronidating systems. Activation of glucuronidation by harmol at high concentration can be excluded.

Topics: Alkaloids; Animals; Cholestasis; Glucuronates; Harmine; Kinetics; Liver; Male; Metabolic Clearance Rate; Nitrophenols; Rats; Rats, Inbred Strains; Sulfates