Selective induction of phase II drug metabolizing enzyme activities by quinolines and isoquinolines.
Rats treated with quinoline, and to a lesser extent, isoquinoline (75 mg/kg, daily for 3 days) showed induction of phase II drug metabolizing enzyme activities without inducing either cytochrome P450 concentration or CYP1A-, CYP2B-, CYP2E-, and CYP3A-selective activities. Elevations of UDP-glucuronosyltransferase activities towards 4-nitrophenol, 1-naphthol, and morphine elicited by quinoline (1.9- to 2.7-fold), were greater than those elicited by isoquinoline (1.4- to 1.8-fold). UDP-glucuronosyltransferase activities towards estrone and testosterone were not increased by either compound. Microsomal epoxide hydrolase activity was increased only by quinoline (2.7-fold). NAD(P)H quinone oxidoreductase activity was increased 2-fold by quinoline and isoquinoline. Cytosolic glutathione S-transferase (GST) activity was increased similarly (approximately 20%) by both agents. Similar treatment of rats with either quinine (75 mg/kg) or chloroquine (150 mg/kg) increased 1-naphthol glucuronidation and GST (quinine only) activities. At 75 mg/kg, chloroquine did not affect any phase II enzyme activities but caused a minor elevation of a phase I enzyme, CYP1A; ascertained from an elevation of 7-ethoxyresorufin deethylase activity and a small hypsochromic shift to the absorbance maximum of the cytochrome P450 CO-complex. With quinoline and isoquinoline treatments (n = 14), the correlation coefficients (R) between microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities towards 4-nitrophenol and morphine were 0.96 and 0.92 respectively, suggesting a highly coordinated induction. The highest NAD(P)H quinone oxidoreductase correlations were with microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities towards 4-nitrophenol and morphine (R approximately 0.78). Correlation coefficients between GST and microsomal epoxide hydrolase and NAD(P)H quinone oxidoreductase activities were approximately 0.49. Quinoline and isoquinoline, nitrogen heterocyclic analogs of naphthalene, join the list of simple nitrogen-containing polycyclic aromatic agents capable of selective induction of phase II drug metabolizing enzymes. The position of the single heterocyclic nitrogen atom in the bicyclic ring influences the magnitude and breadth of the induction response. The addition of bulky ring substituents (quinine, chloroquine) reduced the induction response.
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Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, USA.
Franklin
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D000818:Animals; D002738:Chloroquine / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000096:biosynthesis; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D005982:Glutathione Transferase / Q000096:biosynthesis; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011803:Quinine / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007546:Isoquinolines; D004364:Pharmaceutical Preparations; D011804:Quinolines; D002738:Chloroquine; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; C037219:quinoline; D016660:NAD(P)H Dehydrogenase (Quinone); D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; C039109:isoquinoline