title: Induction and inhibition of the in vitro N1-oxidation of 9-benzyladenine and isomeric 9-(nitrobenzyl)adenines.
abstract: The present study investigated some aspects of the enzymology of the in vitro N1-oxidation of 9-benzyladenine (BA) and isomeric 9-(nitrobenzyl)adenines (NBAs) using various potential inducers and inhibitors of cytochrome P-450 (CYP). When incubated with phenobarbital-induced rabbit hepatic microsomes, the N1-oxidation rates of BA and 9-(4-nitrobenzyl)adenine were about 6- and 2-fold higher than that of the control, respectively; while the N1-oxidation of 9-(2-nitrobenzyl)adenine and 9-(3-nitrobenzyl)adenine was not markedly affected. In contrast, beta-naphthoflavone and Arochlor 1254 showed no inductive effects towards the N1-oxidation of any of these substrates. Using 12 typical CYP inhibitors, it was found that nifedipine (CYP3A inhibitor) and haloperidol (CYP2D inhibitor) showed significant inhibition towards the N1-oxidation of BA and NBAs. Therefore, the N1-oxidation of BA and NBAs is probably catalysed by CYP3A and CYP2D subfamilies. Furthermore, when 9-(4-nitrobenzyl)adenine was incubated with compounds which possessed a certain chemical similarity to the adenine substrate, various degrees of inhibition of N1-oxidation of 9-(4-nitrobenzyl)adenine were observed. These observations allowed a preliminary indication as to the structure-metabolism relationship of 9-substituted adenine derivatives.
authors.affiliation: Chelsea Department of Pharmacy, King's College London, University of London, UK.
authors.forename: D Y
authors.initials: DY
authors.lastname: Liu
authors.forename: J W
authors.initials: JW
authors.lastname: Gorrod
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D006224:Cricetinae; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D011817:Rabbits
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C055872:9-benzyladenine; D003577:Cytochrome P-450 Enzyme System; D000225:Adenine