These results indicate that a lack of *NO production by iNOS caused significantly enhanced cardiac injury. However, when iNOS (-/-) mice were crossed with manganese superoxide dismutase (MnSOD)-overexpressing animals, mitochondrial injury was ameliorated to the level of the wild type. These findings suggest that reduction of *NO levels mediated by ADR treatment leads to increased cardiac mitochondrial injury that can be attenuated by a compensatory increase in MnSOD.

Nutraceuticals are widely used by the general public, but very little information is available regarding the effects of nutritional agents on drug toxicity. Excessive doses of acetaminophen (APAP, 4-hydroxyacetanilide) induce hepatic centrilobular necrosis. The naturally occurring substance S-adenosyl-L-methionine (SAMe) has been reported to reduce the hepatic toxicity of APAP. The present study was designed to investigate the hepatoprotective effects of SAMe in comparison to the clinically used antidote N-acetylcysteine (NAC). Male C57BL/6 mice were injected intraperitoneally (i.p.) with an equimolar dose (1.25 mmol/kg) of either SAMe or NAC just before APAP, and the groups were denoted SAMeϩAPAP and NACϩAPAP, respectively. Mice were immediately injected i.p. with 300 mg/kg APAP, and hepatotoxicity was evaluated after 4 h. SAMe was more hepatoprotective than NAC at a dose of 1.25 mmol/kg as liver weight was unchanged by APAP injection in the SAMeϩAPAP group, whereas liver weight was increased in the NACϩAPAP group. SAMe was more hepatoprotective for APAP toxicity than NAC, because alanine aminotransferase levels were lower in the SAMeϩAPAP. Pretreatment with SAMe maintained total hepatic glutathione (GSH) levels higher than NAC pretreatment before APAP, although total hepatic GSH levels were lower in the SAMeϩAPAP and NACϩAPAP groups than the vehicle control values. Oxidative stress was less extensive in the SAMeϩAPAP group compared with the APAPtreated mice as indicated by Western blots for protein carbonyls and 4-hydroxynonenal-adducted proteins. In summary, SAMe reduced APAP toxicity and was more potent than NAC in reducing APAP hepatotoxicity.

Retinoids are signaling molecules that are involved in proliferation, differentiation and apoptosis during development. Retinoids exert their effects, in part, by binding to nuclear receptors, thereby altering gene expression. Clinical use of retinoids in the treatment of neuroblastoma is of interest due to their success in management of acute promyelocytic leukemia. Using the SK-N-SH human neuroblastoma cell line we investigated the effect of the differentiation agent, all-trans-retinoic acid (ATRA) on manganese superoxide dismutase (MnSOD) expression, an enzyme previously shown to enhance differentiation in vitro. Manganese superoxide dismutase mRNA, protein and activity levels increased in a time dependent manner upon treatment with ATRA. Nuclear levels of the NFκB proteins, p50 and p65, increased within 24 h of ATRA administration. This increase paralleled the degradation of the cytoplasmic inhibitor, IκB-β. Furthermore an increase in DNA binding activity to a NFκB element occurred within a 342 base pair enhancer (I2E) of the SOD2 gene with 10 μM ATRA treatment. Reporter analysis showed that ATRA-mediated I2E dependent luciferase expression was attenuated upon mutation of the NFκB element, suggesting a contribution of this transcription factor in retinoid-mediated upregulation of MnSOD. This study identifies SOD2 to be a retinoid responsive gene and demonstrates activation of the NFκB pathway in response to ATRA treatment of SK-N-SH cells. These results suggest signaling events involving NFκB and SOD2 may contribute to the effects of retinoids used in cancer therapy.

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