ELEVATION OF ALDOSE REDUCTASE GENE-EXPRESSION IN RAT PRIMARY HEPATOMA AND HEPATOMA-CELL LINES - IMPLICATION IN DETOXIFICATION OF CYTOTOXIC ALDEHYDES

Aldose reductase and aldehyde reductase are members of the aldo-keto reductase superfamily, and participate in the reduction of a wide range of carbonyl compounds. We have purified aldose reductase from rat lens and raised antiserum against it in rabbits. Immunoblot analyses using this antibody showed that a significant amount of aldose reductase was expressed in cell lines derived from hepatomas while it was negligible in normal hepatocytes. Elevated expression of aldose reductase was also observed in cancerous lesions of 3'-methyl-4-dimethyl-aminoazobenzene (3'-Me-DAB)-induced hepatocarcinomas. Expression of aldose reductase mRNA was confirmed in these cells by Northern-blot analysis, suggesting that the induction occurred at the stage of gene transcription. The level of aldehyde reductase, however, did not change in cancerous tissue or in the cell lines. The viability of hepatoma cells in the presence of 8-deoxyglucosone and glyceraldehyde was decreased by an aldose reductase inhibitor, ONO-2235 (5-[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3- thiazolidineactic acid). Taken together, induction of aldose reductase gene expression during hepatocarcinogenesis may render cancer cells resistant to various toxic carbonyl compounds produced during metabolism or administered as anti-cancer drugs. (C) 1995 Wiley-Liss, Inc.