Inhibition of p-nitrophenol hydroxylase in rat liver microsomes by small aromatic and heterocyclic molecules.
The cytochrome P450 isoenzyme P4502E1 is constitutively expressed in human liver and catalyzes the oxidation of many known or suspected carcinogens of low molecular weight. In this structure-metabolism study, the role that heteroatoms in heterocyclic compounds play in determining their affinity for P4502E1 was investigated. The ability of 16 six-membered and 10 five-membered compounds to inhibit the hydroxylation of p-nitrophenol, which is specifically catalyzed by P4502E1, was studied in suspensions of microsomes from rat livers in which P4502E1 had been induced by inclusion of acetone in the drinking water. Apparent Ki values were extrapolated from kinetic models of Dixon or Cornish-Bowden plots for enzyme inhibition. Enzyme inhibition was generally of the non-or uncompetitive type. Pyridine was the most potent and benzene one of the least potent inhibitors, with Ki values of 0.4 microM and 8,400 microM, respectively. Pyridazine was less inhibitory than 1,3,5-triazine, which inhibited P4502E1 to a lesser degree than pyrazine and pyrimidine. Among the unsubstituted unsaturated five-membered ring molecules, pyrrole was a better inhibitor than furan or thiophene. 4-Methylimidazole was a much stronger inhibitor than imidazole or 1-and 2-methylimidazole. The ability of compounds to inhibit P4502E1 seems to depend in the main on the presence of a nitrogen atom in the molecule and on the ability of the nitrogen lone pair of electrons to ligand to the heme.
Medical Research Council Toxicology Unit, University of Leicester, UK.
M B
MB
Hargreaves
B C
BC
Jones
D A
DA
Smith
A
A
Gescher
D000818:Animals; D002396:Catechols / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006838:Hydrocarbons / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002396:Catechols; D065607:Cytochrome P-450 Enzyme Inhibitors; D006571:Heterocyclic Compounds; D006838:Hydrocarbons; D009596:Nitrophenols; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C001833:4-nitrocatechol; C024836:4-nitrophenol