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PJ Ciaccio, JE Stuart and KD Tew
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
We report the initial identification of a 37.5-kDa putative aldoketo reductase in human colon carcinoma cells. An aminoterminal trypsin fragment was sequenced and found to be identical to bovine prostaglandin F synthase in 19 of 21 amino acids. Levels of this cytosolic human aldo-keto reductase, assessed by immunoblots using polyclonal antibodies raised against this protein, increased 30-fold in cells resistant to the Michael reaction acceptor ethacrynic acid and increased with time and ethacrynic acid concentration after treatment of wild-type cells. Induction of the reductase appeared to be cell type and drug specific. It was induced by the Michael reaction acceptors dimethyl maleate, t-butylhydroquinone, and hydroquinone but not by the nitrogen mustard chlorambucil. Ethacrynic acid and dimethyl maleate induced the reductase in a second human colon cell line but not in human prostate cells. NADPH-dependent metabolism of aldoketo reductase substrates by cytosol from colon but not prostate cells was enhanced 2- 3-fold when cells were grown in the presence of either ethacrynic acid or dimethyl maleate. The discrepancy between induced reductase activity and protein levels may be due to the multiplicity of constitutively expressed NADPH-dependent reductases that compete for substrate. Ethacrynic acid-resistant cells exhibited low levels of cross- resistance to Adriamycin, mitomycin C, and the bovine prostaglandin F synthase substrates phenylglyoxal and prostaglandin D2. Thus, significant overexpression of a human aldo-keto reductase structurally related to bovine prostaglandin F synthase may result from exposure of cells to Michael reaction acceptors and may give rise to an enhanced capacity to metabolize exogenous and endogenous substrates, thereby contributing to the drug-resistant phenotype.
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