Aldo-keto reductase-7A (AKR7A) is an enzyme important for bioactivation and biodetoxification. Previous studies suggested that Akr7a 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, N-acetyl-p-benzoquinoneimine (NAPQI). This study was, therefore, carried out to investigate whether Akr7a is involved in the protection against APAP-induced oxidative stress and hepatotoxicity. We found that in response to APAP or NAPQI exposure, Akr7a3 mRNA and protein were significantly up-regulated in vitro in human HepG2 and LO2 cells. Similarly, strong induction was observed for Akr7a5 in mouse AML12 hepatocytes exposed to APAP. In vivo 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 Akr7a3, suggesting that Nrf2, indeed, contributes significantly to the induction of Akr7a. 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 Akr7a5 in vitro in cultured AML12 cells or depletion of Akr7a1 in vivo in rat liver greatly increased APAPinduced hepatotoxicity. Conclusion: 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. (HEPATOLOGY 2011;54:1322-1332 A cetaminophen (also called paracetamol, N-acetyl-p-aminophenol, Tylenol V R , and APAP) is a clinically widely used drug with potent analgesic and antipyretic activities. At therapeutic doses, most ingested APAP is metabolized to phenolic glucuronide and sulfate conjugates in the liver by glucuronyltransferases and sulfotransferases and is subsequently excreted in the urine 1 ; however, a small portion is oxidized by cytochrome P450 (CYP450) 2E1 to generate a highly reactive, cytotoxic intermediate: N-acetyl-pAbbreviations: AFAR, aflatoxin aldehyde reductase; AKR, aldo-keto reductase; AKR7A, aldo-keto reductase-7A; ALT, alanine aminotransferase; APAP, acetaminophen; ARE, anti-oxidant response element; AST, aspartate transaminase; Cat, catalase; CMV, cytomegalovirus; CYP450, cytochrome P450; DMSO, dimethylsulfoxide; ERE, estrogen response element; G6PDH, glucose-6-phosphate dehydrogenase; Gpx-1/2, glutathione peroxidase-1/2; GSH, glutathione; GST, glutathione S-transferase; IDH-1,...

Acetaminophen (APAP) a commonly used drug for decrease the fever and pain but is capable to induced hepatotoxicity at over dose. This study was carried out to investigate the effect of APAP on the expression of antiapoptotic and antioxidative defense genes, and whether aldose reductase over-expressing plasmid capable to protect against APAP-induced oxidative stress and cell death. APAP treatment induced oxidative stress and hepatotoxicity, and significantly increased aldose reductase mRNA and protein expression in mouse hepatocyte (AML-12).Unexpectedly, AML-12 cells over-expressing aldose reductase augmented APAP-induced reduction in cell viability, reactive oxygen species (ROS) production, glutathione (GSH) depletion and glutathione S-transferase A2 expression. Moreover, over-expression of aldose reductase potentiated APAP induced reduction on proliferating cell nuclear antigen, B cell lymphoma-extra large (bcl-x L ), catalase, glutathione peroxidase-1 (GPx-1) and abolished APAP-induced B-cell lymphoma 2 (bcl-2) inductions. Further, over-expression of aldose reductase significantly abolished AMP activated protein kinase (AMPK) activity in APAP-treated cells and induced p53 expression. This results demonstrate that APAP induced toxicity in AML-12, increased aldose reductase expression, and over-expression of aldose reductase render this cell more susceptible to APAP induced oxidative stress and cell death, this probably due to inhibition AMPK or bcl-2 activity, or may due to competition between aldose reductase and glutathione reductase for NADPH.

Many countries in the world wide banned hydroquinone in cosmetics skin lightening but it is still used in most of Africa countries, including Sudan. Few studies were carried out on the side effect of hydroquinone on Sudanese women. Therefore, the present study was carried out in Khartoum state in April to May/2014 to assess the awareness of Sudanese women about using hydroquinone and its probable risks. The results revealed that, highly using cosmetics containing hydroquinone by women aged between 20 -29 years (78.3%) as well as by those classified as single (69.6%). The results also showed that the highest percentage of women was using it during evening (81.2%) and a high percentage of them was using it for skin lightening (65.2%), followed by elimination acne (20.3%) and about 10.1% for both skin lightening and elimination of acne and very little (4.3%) for freckle elimination. Moreover, the results showed a very high percentage of women (94.2%) used the chemical without being prescribed by doctors and about (85.5%) of them didn't know its nature and risks on human health. Consequently, (50.7%) of women have had sides effects, (44.9 %) used more than one and (44.1%) used it regularly. In addition, the results revealed that a wide range of products of this chemical was available in local market with amalico (34.8%) being highly used. The study can conclude that the awareness of Sudanese women about this compound was poor and needs to be raised by health authorities.