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

Abstract
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.
AuthorsK R Krijgsheld, H J Koster, E Scholtens, G J Mulder
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 221 Issue 3 Pg. 731-4 (Jun 1982) ISSN: 0022-3565 [Print] United States
PMID7086685 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Alkaloids
  • Glucuronates
  • Sulfates
  • harmol
  • Harmine
Topics
  • Alkaloids (metabolism)
  • Animals
  • Cholestasis (chemically induced, prevention & control)
  • Diet
  • Glucuronates (metabolism)
  • Harmine (analogs & derivatives, metabolism, pharmacology)
  • Liver (metabolism)
  • Male
  • Rats
  • Rats, Inbred Strains
  • Sulfates (metabolism)
  • Time Factors

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