Effect of 1,3-bis-(2-chloroethyl)-1-nitrosourea on cholephilic dye metabolism and excretion in anesthetized rats.
The maximal biliary excretion of sulfobromophthalein (BSP) during constant i.v. infusion (2.5 mg/min/kg) was inhibited 45% in pentobarbital-anesthetized Sprague-Dawley rats, 48 hr after treatment with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU; 20 mg/kg i.p.). Thirty-six to 48 hr after treatment, BCNU also inhibited the biliary excretion of an i.v. bolus of indocyanine green (24 mg/kg) by 75 to 85%. This suggested that inhibition of glutathione-S-transferase activity was not the main site of action of BCNU in its interference with cholephilic dye excretion. Indeed, it was found that conjugation of BSP with reduced glutathione (GSH) mediated by liver cytosol isolated from BCNU-pretreated rats was unaltered. In addition, BCNU did not deplete hepatic GSH. On the contrary, the hepatic concentration of GSH was increased by 60% 48 hr after treatment with BCNU. Thus, the ability of BCNU to block BSP excretion is probably not due to decreased conjugation of BSP with GSH. Inhibition of excretion under the saturating conditions of constant infusion strongly suggests an effect on canalicular excretion.
Hoyt
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Department of Pharmacology and Toxicology, College of Pharmacy, Oregon State University, Corvallis.
Larson
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D000758:Anesthesia; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D002330:Carmustine / Q000494:pharmacology*; D004137:Dinitrochlorobenzene / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007208:Indocyanine Green / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013448:Sulfobromophthalein / Q000378:metabolism
D004137:Dinitrochlorobenzene; D013448:Sulfobromophthalein; D005978:Glutathione; D007208:Indocyanine Green; D002330:Carmustine