Cholestatic effect of harmol glucuronide in the rat. Prevention of harmol-induced cholestasis by increased formation of harmol sulfate

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 221; no. 3; p. 731
• Main Authors: Krijgsheld, K R, Koster, H J, Scholtens, E, Mulder, G J
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.06.1982
• Subjects: Alkaloids - metabolism; Animals; Cholestasis - chemically induced; Cholestasis - prevention & control; Diet; Glucuronates - metabolism; Harmine - analogs & derivatives; Harmine - metabolism; Harmine - pharmacology; Liver - metabolism; Male; Rats; Rats, Inbred Strains; Sulfates - metabolism; Time Factors
• ISSN: 0022-3565; 1521-0103

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.