Requirement of cellular uptake for adenosine inhibition of p-nitrophenol glucuronidation in isolated rat hepatocytes.
Adenosine (ADO) has been shown previously to inhibit p-nitrophenol glucuronidation in a concentration-dependent manner when concurrently incubated in isolated rat hepatocytes for 30-60 min. In the current study, preincubation of ADO (500 microM) in isolated hepatocytes for 30 min prior to addition of 100 microM p-nitrophenol resulted in a greater inhibition of glucuronidation when compared to that without preincubation (80 vs 50% inhibition). The inhibitory effect of 250 microM ADO on glucuronidation was decreased from 60 to 10% in the presence of the ADO transport inhibitor nitrobenzyl thioinosine during the 30-min preincubation period. Without prior incubation, 100 microM dibutyryl cyclic AMP (DBcAMP) produced an inhibition of glucuronidation similar to that of 500 microM ADO. In contrast to ADO, there was no significant difference in the inhibitory effect of DBcAMP on p-nitrophenol glucuronidation with or without a 30-min preincubation. Thus, DBcAMP and ADO appear to inhibit glucuronidation through different mechanisms. Furthermore, these results indicate that the inhibitory effect of ADO on p-nitrophenol glucuronidation is dependent to a large degree on the cellular uptake of ADO into hepatocytes, while a portion of the inhibitory effect may arise from the generation of intracellular cyclic AMP.
Meng
Y
Y
Department of Pharmacology and Toxicology, University of Maryland School of Pharmacy, Baltimore 21201.
Weiner
M
M
D000241:Adenosine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009596:Nitrophenols / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014535:Uridine Diphosphate Glucuronic Acid / Q000737:chemistry / Q000378:metabolism*
D009596:Nitrophenols; D014535:Uridine Diphosphate Glucuronic Acid; D013868:Thioinosine; D003994:Bucladesine; C001789:4-nitrobenzylthioinosine; D000241:Adenosine; C024836:4-nitrophenol