Drug metabolizing enzyme induction by simple diaryl pyridines; 2-substituted isomers selectively increase only conjugation enzyme activities, 4-substituted isomers also induce cytochrome P450.
Pyridine derivatives bearing aryl containing substitutions at the 2- and 4-position were administered to male rats, daily, for 3 days at 75 mg/kg. All five 2-substituted pyridines investigated increased rat hepatic UDP-glucuronosyltransferase activities toward three aglycones (morphine, p-nitrophenol, and 1-naphthol) without inducing cytochrome P450. Two of the 4-substituted pyridines investigated (4,4'-dipyridyl, 4-benzylpyridine) significantly induced cytochrome P450. UDP-glucuronosyl-transferase activity by the 4-substituted pyridines was increased to a much lesser extent than seen for the equivalent 2-isomers. The two 4-substituted pyridines eliciting induction of cytochrome P450 were also the only 4-isomers which increased cytosolic glutathione-S-transferase activity, but three 2-substituted pyridines (2-benzoylpyridine, 2-benzylpyridine, and trans-1,2-bis(2-pyridyl)ethylene) increased this activity in the absence of cytochrome P450 induction. No compound investigated induced cytosolic sulfotransferase activity. Diaryl compounds lacking a heterocyclic ring did not increase any of the investigated drug metabolizing enzyme activities. For simple diarylpyridines, the position of substitution on the pyridine ring rather than the nature of the substituent appears to be a major determinant for selective induction of UDP-glucuronosyltransferases without concurrent increases in cytochrome P450. The 2-substituted pyridines were consistently selective inducers of only Phase II or conjugation enzymes. The 4-substituted pyridines included derivatives that could selectively induce Phase II and nonselectively induce both Phase I and Phase II and one derivative that induced neither.
Franklin
M R
MR
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects; D004790:Enzyme Induction; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009020:Morphine / Q000378:metabolism; D009284:Naphthols / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D009284:Naphthols; D009596:Nitrophenols; D011725:Pyridines; C029350:1-naphthol; D009020:Morphine; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; C024836:4-nitrophenol