Cholestatic effect of harmol glucuronide in the rat. Prevention of harmol-induced cholestasis by increased formation of harmol sulfate.
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.
D000470:Alkaloids / Q000378:metabolism*; D000818:Animals; D002779:Cholestasis / Q000139:chemically induced* / Q000517:prevention & control; D004032:Diet; D005965:Glucuronates / Q000378:metabolism; D006247:Harmine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism; D013997:Time Factors
D000470:Alkaloids; D005965:Glucuronates; D013431:Sulfates; C001326:harmol; D006247:Harmine