Enzymology of the reduction of the novel fused pyrazine mono-n-oxide bioreductive drug, RB90740 roles for P450 reductase and cytochrome b5 reductase

Biochemical Pharmacology
H M Barham, I J Stratford

Abstract

RB90740 is the lead compound in a series of fused pyrazine mono-N-oxide bioreductive drugs. Theses agents have potential application in cancer therapy, since they are more toxic to hypoxic than to aerobic cells as a consequence of their bioactivation by cellular reductase enzymes within the hypoxic regions of a tumour. In this study, mouse liver microsomes have been used to characterise the enzymology of the reductive activation of RB90740. Under hypoxic conditions, the reduction of RB90740 to its stable 2-electron reduced product RB92815 was supported by both NADH and NADPH, the former supporting a rate approximately 80% of the latter. Combining the two cofactors had no additive effect. Neither carbon monoxide nor metyrapone inhibited reduction of RB90740, indicating that P450 isozymes were not involved in the reduction of this compound. 2' AMP, and inhibitor of P450 reductase, did not inhibit formation of RB92815, whereas DPIC, another inhibitor but with a different mode of action, inhibited both the NADH, and NADPH-dependent reduction of RB90740. Similarly, two selective inhibitors of NADH: cytochrome b5 reductase, pHMB and PTU, completely inhibited both NADH and NADPH-dependent reduction of RB90740. Our findings implicate P...Continue Reading

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Citations

Oct 16, 2001·European Journal of Medicinal Chemistry·W A Denny
Mar 1, 2000·Drug Metabolism and Drug Interactions·L SkálováE Kvasnicková
Aug 9, 2008·Medicinal Research Reviews·Yu Chen, Longqin Hu
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Dec 12, 2019·Biochimica Et Biophysica Acta. Bioenergetics·Gabriel N ValérioAlejandro K Samhan-Arias

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