Cytochrome P450 reductases (CPR) belong to a family of electron transfer flavoproteins that cooperates with cytochromes P450 (P450) and supplies reducting equivalents required for catalysis by these enzymes. Compounds C-857 and C-1748 belong to the new set of antitumor 9-amino-1‑nitroacridine derivatives developed in our Department. One of them, C-1748 (Capridine-beta^R) which expressed low toxicity in animals and potent antitumor activity against prostate cancer is selected to Phase I clinical trials.

We showed earlier that the metabolic activation of 1‑nitroacridines is necessary for activity of these compounds towards tumor cells. Furthermore, less toxic compound, C-1748 was less reactive with microsomes and recombinant CPR than C-857 was. The preliminary results of metabolism with recombinant P450 isoenzymes (CYPs) of low CPR levels demonstrated that incubations of C-1748 yielded identical metabolites for all CYPs except CYP1A2. Whereas, incubations of C-857 did not result in any differences between metabolites formed with all studied CYPs.

In order to elucidate the role of CPR in metabolism of C-857 in comparison with that of C‑1748, we carried out and present here the studies on (i) metabolic transformations with selected E. coli recombinant human CYPs of high and low levels of CPR and (ii) metabolism with microsomes of hepatic CPR null mice. The obtained incubation mixtures were analyzed

by RP-HPLC. UV-vis and ESI-MS spectra collected for chromatographic peaks and compared with those of model compounds let us identify the structures of metabolites. The results confirmed that the different metabolic products formed with CYP1A2 were observed only for less toxic C-1748 not for C-857. The differences between compounds were much more clear in the case of high than of low level of CPR coexpressed with CYPs. The latter results together with the studies with microsomes of hepatic CPR null mice strongly indicate the crucial role of CPR in toxic action of the studied potent antitumor drug C-1748.

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