Metabolic activation of adriamycin by NADPH-cytochrome P450 reductase; overview of its biological and biochemical effects

NADPH-cytochrome P450 reductase (P450 reductase) is one of the enzymes impli­cated in the metabolism of adriamycin, a very important clinically used antitumour drug. However, apart from the enzyme involvement, so far little was known about the chemical route and biochemical effects of this process. We demonstrated that the ap­plication of P450 reductase simultaneously with adriamycin to tumour cells in culture significantly increased cytotoxicity of the drug. Under tissue culture conditions, we noticed also that, in the presence of P450 reductase, adriamycin metabolite(s), dis­playing an altered spectrum within the visible light range were formed. This observa­tion was taken adavantage of to study the metabolism of adriamycin in cell-free sys­tems, using initially the enzyme isolated from rat liver and the recently obtained re­combinant human P450 reductase. The reductive conversion of the drug turned out to be a multi-stage process, which occurred only under aerobic conditions and was ac­companied by excessive NADPH consumption. Further research carried out with the aid of radical scavengers and radiolabelled adriamycin revealed that the enhance­ment of biological activity of adriamycin by P450 reductase stemmed from the forma­tion of alkylating metabolite(s) rather than from the promotion of redox cycling known to be induced in the presence of anthracyclines.