Heterogeneity of anthracycline antibiotic carbonyl reductases in mammalian livers

Abstract

The anticancer antibiotics, daunorubicin and adriamycin, are reduced to their corresponding alcohol and glycol metabolites by cytoplasmic carbonyl reductases occurring in human, rabbit, rat and mouse tissues. Our data indicate that at least two different groups of pH-dependent daunorubicin reductases occur in rabbit and human liver: (1) the pH activity profile for daunorubicin reductases shows distinct optima or significant activity at both pH 6.0 and 8.5, and (2) pH 8.5-dependent daunorubicin reductases are resolved from pH 6.0-dependent daunorubicin reductases by ion exchange chromatography on DEAE-cellulose columns, gel filtration chromatography on BioGel P150, and isoelectric focusing. Ion exchange chromatography and isoelectric focusing also resolve multiple forms of each class of activities. A similar analysis suggests that a single type of pH-dependent daunorubicin reductase occurs in rat and mouse livers: (1) rat and mouse livers show a single pH optima for daunorubicin at pH 8.5, and (2) isoelectric focusing of rat and mouse preparations confirms the existence of a pH 8.5 daunorubicin and the absence of significant pH 6.0 daunorubicin activity. Although total adriamycin reduction is lower than daunorubicin reduction at any pH, significant adriamycin reduction also occurs in rabbit liver at pH 6.0 and 8.5; however, neither of these activities can be distinguished from pH 6.0 daunorubicin reductase activity by ion exchange and gel filtration chromatography and isoelectric focusing. In comparison, very low levels of pH 6.0 optimum adriamycin reductase activity are seen in human, rat and mouse livers. Thus, all species have pH 8.5 daunorubicin reductase and probably pH 8.5 adriamycin reductase, whereas rabbit and human also have pH 6.0 daunorubicin reductase(s) and rabbit has a pH 6.0 adriamycin reductase(s), which accounts for the bulk of the active anthracycline antibiotic metabolism in these species.