Intestinal absorption of S-(pentachlorobutadienyl)glutathione and S-(pentachlorobutadienyl)-L-cysteine, the glutathione and cysteine S-conjugates of hexachlorobuta-1,3-diene.
The bioactivation of the nephrotoxin hexachlorobuta-1,3-diene (HCBD) involves hepatic formation and biliary excretion of S-(pentachlorobutadienyl)glutathione (PCBG). The intestinal absorption of PCBG was studied in vivo by introducing PCBG or its metabolite, S-(pentachlorobutadienyl)-L-cysteine (PCBC), into rat intestines via a biliary cannula and measuring PCBG and PCBC concentrations in portal blood. When PCBG was infused into the intestine, both PCBG and PCBC were found in the blood; the highest metabolite concentrations (0.9 nmol/ml for PCBG and 1 nmol/ml for PCBC) were observed 30 min after infusing the S-conjugate. Higher blood PCBC concentrations were observed after PCBC infusion than after PCBG infusion. Transport studies in CaCo-2 cells, a human intestinal cell line, showed that application of PCBG (0.1 mM) to the apical side of the cells resulted in a 2.4-fold accumulation of PCBG in the basolateral chamber after 24 hr; in this time, the cells metabolized 69% of the applied PCBG to PCBC. Addition of glutathione (1 mM), gamma-glutamyl-p-nitroanilide (1 mM), or probenecid (1 mM) to the apical chamber diminished the active transport of PCBG. With PCBC, no active apical or basolateral transport was observed. The experiments are the first demonstration of the intestinal absorption of the S-conjugates of HCBD, which is an important step in their translocation from the liver to the kidney.
Department of Pharmacology, University of Rochester, NY 14642.
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Gietl
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Vamvakas
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Anders
D000818:Animals; D002070:Butadienes / Q000493:pharmacokinetics*; D002460:Cell Line; D003545:Cysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D002070:Butadienes; D007555:Isoxazoles; C039330:S-pentachlorobuta-1,3-dien-yl-cysteine; C050500:S-(1,2,3,4,4-pentachloro-1,3-butadienyl)glutathione; C001335:hexachlorobutadiene; D005978:Glutathione; D003545:Cysteine; C006303:acivicin; D011339:Probenecid