Matrix metalloproteinase-9, -10, and -12, MDM2 and p53 expression in mouse liver during dimethylnitrosamine-induced oxidative stress and genomic injury.

Treatment during early tumor development has greater success because tissue growth remains largely confined to its original locus. At later stages, malignant cells migrate from their original location, invade surrounding normal areas, and can disseminate widely throughout the body. Remodeling of the extracellular matrix (ECM) serves as a key facilitator of this dissemination. Proteolytic enzymes including plasmin and matrix metalloproteinases (MMPs) play an integral role in degrading the surrounding ECM proteins and clearing a path for tumor cell migration. Specific MMPs are highly expressed late during malignant tumor invasion. It is not understood whether early changes in MMPs influence apoptotic and necrotic cell death, processes known to govern the early stages of carcinogenesis. Similarly, the interaction between MDM2 and p53 is tightly controlled by a complex array of post-translational modifications, which in turn dictates the stability and activity of both p53 and MDM2. The present studies examine the hypothesis that model hepatotoxin dimethylnitrosamine (DMN), which is also a model carcinogen, will induce the MMP family of proteins after administration in hepatotoxic doses. Doses of 25, 50, and 100 mg/kg DMN were administered i.p. to male C3H mice. Changes in parameters associated with apoptotic and necrotic cell death, DNA damage, cell proliferation, and extracellular proteinases were examined in liver at 24 h. Serum ALT activity, oxidative stress [malondialdehyde], and caspase-activated DNAse mediated DNA laddering increased in a dose-dependent manner, as did the level of MDM2 protein. MMP-9, -10 and -12 (gelatinase-B, stromelysin-2, macrophage elastase), and p53 protein levels increased following 25 mg/kg DMN, but were successively decreased after higher DMN doses. The results of this study demonstrate changes in MDM2 and MMPs during DMN-induced acute liver injury and provide a plausible linkage between DMN-induced oxidative stress-mediated genomic injury and its likely involvement in setting the stage for initiating subsequent metastatic disease at later circumstances.

Long term exposure effect of a unique metabolic nutrition system containing a diverse group of phytochemicals on serum chemistry and genomic and non-genomic changes in the liver of female B6C3F1 mice.

The nutritional value and therapeutic benefits coupled with presumed safety have heightened interest in the use of custom designed dietary supplements. Their use has increased substantially since the passage of the 1994 Dietary Supplement Health Education Act. However, few well-controlled studies have been conducted to assess the safety and potential adverse effects of dietary supplements. MNSO (MNS Orange-AdvoCare) is a unique combination of vitamins, minerals, omega-3 fatty acids and herbal extracts designed to provide a strong foundation of nutritional support, enhance thermogenesis, heighten energy levels and improve immune status. This investigation was designed to explore the safety and toxic effects, if any, of 12 months of continuous exposure to the ephedra and caffeine containing MNSO on serum chemistry and histopathology of seven vital target organs in female B6C3F1 mice. MNSO is enriched with extracts of citrus, Ephedra, Ginkgo, green tea and Ocimum. In this study, mice were fed control (-MNSO) or MNSO (1x-10x, 1x = daily human dose) diets. Blood was collected from all groups including the control every 4 months for serum chemistry analysis (enzyme, lipid, carbohydrate, electrolyte profiles), and liver tissue was collected for tissue biochemistry and histopathology. Multiple biochemical parameters included: (i) determination of oxidative stress via lipid peroxidation and (ii) assessment of genomic integrity via DNA fragmentation. In addition, food consumption and body weight changes were also monitored biweekly. The data showed that 12 months ingestion of 10x-MNSO did not significantly influence organ histopathology, alter the normal serum chemistry profile or any of the crucial tissue biochemistry. MNSO-exposed animals were more active, consumed more food and were relatively leaner compared with the controls. This study indicates that a caffeine and ephedra containing metabolic nutrition system is non-toxic and non-hepatotoxic in mice at up to 10x the human consumption dose of ephedra.