Choleresis and increased biliary efflux of glutathione induced by phenolic antioxidants in rats.
The mechanism by which high doses of the synthetic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) raise hepatic glutathione levels above physiological values was investigated in rats. A single dose of an antioxidant (200 mg/kg; p.o.) reduced the hepatic glutathione content by 17% (BHA) or 36% (BHT) after 5 h, but in contrast levels of 55% (BHA) or 34% (BHT) above controls (7.1 +/- 0.5 mumol GSH-equivalents/g liver wt) were measured 48 h after dosing. Both antioxidants increased basal bile flow (1.37 +/- 0.11 microliter/min per g liver wt) and biliary efflux of total glutathione, i.e. GSH and GSSG, (4.18 +/- 0.97 nmol GSH-eq./min per g) severalfold (up to 250%) over controls 24 h after in vivo antioxidant treatment. The sinusoidal efflux of reduced glutathione (14.9 +/- 2.2 nmol GSH-eq./min per g) was significantly reduced (BHA: 23%; BHT: 41%). The increased glutathione excretion into bile is likely to be independent of the induction of the choleresis. The secretion of bile salts was unaffected by BHA treatment and only temporarily reduced by BHT.


CONCLUSIONS
phenolic antioxidants increase the hepatic turnover of glutathione by stimulating the biliary efflux of GSH. The resulting shift from a predominantly sinusoidal efflux of GSH in controls (hepato-renal circulation) to a predominantly biliary efflux of GSH in antioxidant-treated animals (entero-hepatic circulation) may lead to increased concentrations of cysteine, glycine and glutamic acid in the portal vein and consequently may stimulate the biosynthesis of GSH by enhanced substrate availability in the liver.
Jaeschke
H
H
Physiologisch-chemisches Institut der Universitaet, Tuebingen, F.R.G.
Wendel
A
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001646:Bile / Q000187:drug effects* / Q000378:metabolism; D002083:Butylated Hydroxyanisole / Q000494:pharmacology*; D002084:Butylated Hydroxytoluene / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000975:Antioxidants; D002084:Butylated Hydroxytoluene; D002083:Butylated Hydroxyanisole; D005978:Glutathione