Reductive metabolism of the nitroimidazole-based hypoxia-selective cytotoxin NLCQ-1 (NSC 709257).
The enzymatic cell-free metabolism of the novel hypoxia-selective cytotoxin 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1) was investigated under hypoxic or aerobic conditions in the presence of purified reductive enzymes or isolated rat liver microsomes by monitoring the parent compound with HPLC-UV analysis. Enzymatic reduction of NLCQ-1 with isolated rat liver microsomes and NADPH or NADH showed that, only under hypoxic conditions, ca. 45% and 60% of the parent compound was reduced, respectively, within 1 h of incubation (37 degrees C). Under identical conditions but in the presence of 2'-AMP (a P450 reductase inhibitor), 6-propyl-2-thiouracil or p-hydroxymercuribenzoate (cytochrome b5 reductase inhibitors), NLCQ-1 reduction was inhibited. Enzymatic cell-free metabolism of NLCQ-1 with recombinant human DT-diaphorase (DTD) and NADPH or NADH under hypoxic or aerobic conditions showed that < or = 5% of the compound was reduced within 2 h. Reduction kinetics with human P450 reductase-expressing microsomes showed ca. 75% or 50% reduction of NLCQ-1 under hypoxic or aerobic conditions, respectively, after 2 h incubation. These results suggest that DTD is not involved in the initial steps of the bioreductive metabolism of NLCQ-1, although it could be involved with metabolites of NLCQ-1, and that cytochrome P450 and cytochrome b5 reductases play a significant role in the bioreductive metabolism of NLCQ-1.
Papadopoulou
Maria V
MV
Department of Radiation Medicine at Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA. m-papadopoulou@nwu.edu
Ji
Ming
M
Rao
Mira K
MK
Bloomer
William D
WD
D000249:Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003603:Cytotoxins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009593:Nitroimidazoles / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen; D011804:Quinolines / Q000378:metabolism*; D051381:Rats
C434187:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009593:Nitroimidazoles; D011804:Quinolines; D009243:NAD; D000249:Adenosine Monophosphate; D009249:NADP; D016660:NAD(P)H Dehydrogenase (Quinone); D010100:Oxygen