Dapsone-induced cholestasis and impairment of bile salt output in the rat.
To evaluate the effect of dapsone (4,4'-diaminodiphenylsulfone, DDS) on biliary bile salt secretion, we administered the drug to male and female Wistar rats at a dose of 30 mg/kg body wt, twice a day, for 4 days. DDS decreased basal bile flow by about 20% in both male and female rats. In addition, basal biliary bile salt secretion was decreased by the drug in animals from both sexes (about 30% decrease). Bile salt maximum secretory rate, as evaluated by infusing tauroursodeoxycholate at stepwise-increasing rates, was not affected by DDS in either male or female rats, suggesting that the density of canalicular bile salt transporters is preserved. The size of the bile salt pool and the rate of de novo synthesis of bile salts, measured in bile salt-depleted animals, were decreased by about 33 and 35%, respectively; there was no difference in response between males and females. The ability of the ileum to reabsorb bile salts, as estimated by analysis of the expression of the ileal apical sodium-dependent bile salt transporter and of sodium taurocholate transport activity in brush border membrane vesicles, was not affected by DDS in either males or females. Overall, our findings suggest that an impairment of de novo synthesis mediated by a direct inhibition of CYP3A metabolism, rather than a decreased intestinal reabsorption of bile salts, accounts for the decrease in bile salt pool size. The dissociation between alteration of bile secretory function and the oxidative stress induced by DDS, which is known to be relevant only in male rats, is discussed.
Veggi
Luis M
LM
Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET-U.N.R., Instituto de Fisiología Experimental, Suipacha 570, 2000 Rosario, Argentina.
Crocenzi
Fernando A
FA
Roma
Marcelo G
MG
Dawson
Paul A
PA
Pellegrino
José M
JM
Sánchez Pozzi
Enrique J
EJ
Mottino
Aldo D
AD
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D003622:Dapsone / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D008099:Liver / Q000503:physiopathology; D008708:Methemoglobinemia / Q000139:chemically induced; D008871:Microvilli / Q000378:metabolism; D009929:Organ Size; D029363:Organic Anion Transporters, Sodium-Dependent; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters; D013656:Taurocholic Acid / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001647:Bile Acids and Salts; D015415:Biomarkers; D002352:Carrier Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; D013656:Taurocholic Acid; D003622:Dapsone