Inhibition of glucuronidation and sulfation by dibutyryl cyclic AMP in isolated rat hepatocytes.
Dibutyryl cyclic adenosine 3':5'-monophosphate (DBcAMP) has been reported to cause numerous alterations in the activity of hepatic monooxygenase enzymes following in vivo administration or in vitro addition to intact liver preparations. In the present report the effect of the nucleotide on metabolism of p-nitroanisole (pNA) and aniline was studied in isolated rat hepatocytes. Initial studies indicated that in vitro addition of DBcAMP to hepatocytes increased metabolism of both pNA and aniline as determined by the production of oxidized metabolites, p-nitrophenol (pNP) and p-aminophenol, respectively. After enzymatic hydrolysis with beta-glucuronidase and arylsulfatase, it was determined that DBcAMP had increased accumulation of pNP formed from pNA by inhibiting further metabolism via conjugation reactions. Further studies using pNP directly as substrate confirmed the finding and revealed that glucuronidation was more sensitive to the inhibitory effect of DBcAMP than was sulfation. The 8-bromo derivative of cAMP was more potent than DBcAMP at inhibiting glucuronidation, whereas cyclic AMP and dibutyryl cyclic guanosine 3':5'-monophosphate were without effect. Noncyclic adenine nucleotides (ATP, ADP, AMP) also altered pNA and pNP metabolism. ATP and ADP increased pNP accumulation from pNA while ATP and AMP inhibited glucuronidation of pNP. DBcAMP was further found to decrease UDP-glucuronic acid levels in a concentration-dependent manner without disrupting the redox state (NAD+/NADH) in hepatocytes. The data suggest that adenine nucleotides exert a nonspecific inhibition upon glucuronidation and sulfation reactions.
D000227:Adenine Nucleotides / Q000494:pharmacology; D000627:Aminophenols / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D000840:Anisoles / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology*; D005965:Glucuronates / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009596:Nitrophenols / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism*; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D000227:Adenine Nucleotides; D000627:Aminophenols; D000814:Aniline Compounds; D000840:Anisoles; D005965:Glucuronates; D009596:Nitrophenols; D013431:Sulfates; D014535:Uridine Diphosphate Glucuronic Acid; D003994:Bucladesine; C005306:4-nitroanisole; C026729:4-aminophenol; C023650:aniline; C024836:4-nitrophenol