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An Alternatively Spliced Form of NQO₁ (DT-Diaphorase) Messenger RNA Lacking the Putative Quinone Substrate Binding Site Is Present in Human Normal and Tumor Tissues¹

Arizona Cancer Center, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724

DT-diaphorase is a ubiquitously expressed flavoenzyme responsible for the two-electron reduction of a number of quinone and other anticancer drugs. The majority of DT-diaphorase enzyme activity in human tissues is the product of the NQO₁ gene. We have now identified a novel alternatively spliced form of human NQO₁ mRNA lacking exon 4 at levels equal to or exceeding those of wild-type NQO₁ mRNA. Exon 4 codes for the putative quinone substrate binding site of DT-diaphorase derived from NQO₁ and the recombinant protein from alternatively spliced NQO₁ mRNA lacking exon 4 has minimal enzyme activity with quinoid and other known substrates of DT-diaphorase. The physiological substrate of DT-diaphorase is unknown, and it is possible that the protein derived from the alternatively spliced NQO₁ mRNA could have enzyme activity with an appropriate substrate. We found full-length DT-diaphorase protein but could not detect expression of an appropriately smaller form of DT-diaphorase in human tissues using polyclonal antibody to DT-diaphorase, suggesting that alternatively spliced NQO₁ mRNA lacking exon 4 may not be translated or that the protein product is rapidly degraded. Alternative splicing of NQO₁ RNA could provide an important mechanism for regulating NQO₁ gene expression.

¹ Supported by Public Health Service Grants CA48725 and CA17094 from the National Cancer Institute and a grant from the Charlotte Geyer Foundation.

² To whom requests for reprints should be addressed, at Arizona Cancer Center, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ 85724.

Received 12/ 9/94. Accepted 4/18/95.

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