{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T17:27:56Z","timestamp":1780680476339,"version":"3.54.1"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2011,10,1]],"date-time":"2011-10-01T00:00:00Z","timestamp":1317427200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2011,9,6]],"date-time":"2011-09-06T00:00:00Z","timestamp":1315267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,10]]},"abstract":"<jats:sec><jats:title\/><jats:p><jats:bold>Aldo-keto reductase-7A (AKR7A) is an enzyme important for bioactivation and biodetoxification. Previous studies suggested that<\/jats:bold><jats:bold>Akr7a<\/jats:bold><jats:bold>might be transcriptionally regulated by oxidative stress-responsive transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a protein highly responsive to acetaminophen (APAP) or its intermediate metabolite,<\/jats:bold><jats:bold>N<\/jats:bold><jats:bold>-acetyl<\/jats:bold>-<jats:bold>p<\/jats:bold><jats:bold>-benzoquinoneimine (NAPQI). This study was, therefore, carried out to investigate whether<\/jats:bold><jats:bold>Akr7a<\/jats:bold><jats:bold>is involved in the protection against APAP-induced oxidative stress and hepatotoxicity. We found that in response to APAP or NAPQI exposure,<\/jats:bold><jats:bold>Akr7a3<\/jats:bold><jats:bold>mRNA and protein were significantly up-regulated<\/jats:bold><jats:bold>in vitro<\/jats:bold><jats:bold>in human HepG2 and LO2 cells. Similarly, strong induction was observed for<\/jats:bold><jats:bold>Akr7a5<\/jats:bold><jats:bold>in mouse AML12 hepatocytes exposed to APAP.<\/jats:bold><jats:bold>In vivo<\/jats:bold><jats:bold>in wild-type rats, significant up-regulation of hepatic AKR7A1 protein was observed after administration of APAP. On the other hand, depletion of Nrf2 reduced the expression of<\/jats:bold><jats:bold>Akr7a<\/jats:bold><jats:bold>3, suggesting that Nrf2, indeed, contributes significantly to the induction of<\/jats:bold><jats:bold>Akr7a<\/jats:bold><jats:bold>. Moreover, loss of cell viability in Nrf2-depleted cells was significantly rescued by coexpression of AKR7A3. Furthermore, increased AKR7A3 in HepG2 cells was associated with the up-regulation of oxidative stress-related enzymes to enhance cellular antioxidant defense, which appeared to contribute significantly to protection against APAP-induced toxicity. In a line of transgenic rats overexpressing AKR7A1, increased AKR7A1 stimulated the expression of Nrf2 and other Nrf2-regulated genes, but did not better protect rats from APAP insults. In contrast, depletion of<\/jats:bold><jats:bold>Akr7a5 in vitro<\/jats:bold><jats:bold>in cultured AML12 cells or depletion of<\/jats:bold><jats:bold>Akr7a1 in vivo<\/jats:bold><jats:bold>in rat liver greatly increased APAP-induced hepatotoxicity.<\/jats:bold><jats:bold>Conclusion:<\/jats:bold><jats:bold>AKR7A proteins are significantly up-regulated in response to APAP\/NAPQI exposure to contribute significantly to protection against APAP-induced hepatotoxicity. AKR7A mediates this protection, in part, through enhancing hepatocellular antioxidant defense. 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