Drug Transporter Expression and Localization in Rat Nasal Respiratory and Olfactory Mucosa and Olfactory Bulb

Uptake of drugs and other xenobiotics from the nasal cavity and into either the brain or systemic circulation can occur through several different mechanisms, including paracellular transport and movement along primary olfactory nerve axons, which extend from the nasal cavity to the olfactory bulb of the brain. The present study was conducted to expand knowledge on a third means of uptake, namely the expression of drug transporters in the rat nasal epithelium. We used branched DNA technology to compare the level of expression of nine transporters [(equilibrative nucleoside transporters (ENT)1 and ENT2; organic cation transporter (OCT)1, 2, and 3; OCTN1; organic anion-transporting polypeptide (OATP)3; and multidrug resistance (MRP)1 and MRP4] in nasal respiratory mucosa, olfactory mucosa, and olfactory bulb to the level of expression of these transporters in the liver and kidney. Transporters with high expression in the nasal respiratory mucosa or olfactory tissues were immunolocalized by immunohistochemistry. ENT1 and ENT2 expression was relatively high in nasal epithelia and olfactory bulb, which may explain the uptake of intranasally administered nucleoside derivatives observed by other investigators. OATP3 immunoreactivity was high in olfactory epithelium and olfactory nerve bundles, which suggests that substrates transported by OATP3 may be candidates for intranasal administration

Glutathione-Deficient Mice Are Susceptible to TCDD-Induced Hepatocellular Toxicity but Resistant to Steatosis

2,3,7,8-Tetrachlorodibenzo-<i>p</i>-dioxin (TCDD) generates both hepatocellular injury and steatosis, processes that involve oxidative stress. Herein, we evaluated the role of the antioxidant glutathione (GSH) in TCDD-induced hepatotoxicity. Glutamate-cysteine ligase (GCL), comprising catalytic (GCLC) and modifier (GCLM) subunits, is rate limiting in de novo GSH biosynthesis; GCLM maintains GSH homeostasis by optimizing the catalytic efficiency of GCL holoenzyme. <i>Gclm­(−/−)</i> transgenic mice exhibit 10–20% of normal tissue GSH levels. <i>Gclm­(−/−)</i> and <i>Gclm­(+/+)</i> wild-type (WT) female mice received TCDD for 3 consecutive days and were then examined 21 days later. As compared with WT littermates, <i>Gclm­(−/−)</i> mice were more sensitive to TCDD-induced hepatocellular toxicity, exhibiting lower reduction potentials for GSH, lower ATP levels, and elevated levels of plasma glutamic oxaloacetic transaminase (GOT) and γ-glutamyl transferase (GGT). However, the histopathology showed that TCDD-mediated steatosis, which occurs in WT mice, was absent in <i>Gclm­(−/−)</i> mice. This finding was consistent with cDNA microarray expression analysis, revealing striking deficiencies in lipid biosynthesis pathways in <i>Gclm­(−/−)</i> mice; qrt-PCR analysis confirmed that <i>Gclm­(−/−)</i> mice are deficient in expression of several lipid metabolism genes including <i>Srebp2</i>, <i>Elovl6</i>, <i>Fasn, Scd1/2</i>, <i>Ppargc1a</i>, and <i>Ppara</i>. We suggest that whereas GSH protects against TCDD-mediated hepatocellular damage, GSH deficiency confers resistance to TCDD-induced steatosis due to impaired lipid metabolism

Dietary Whey Protein Lowers the Risk for Metabolic Disease in Mice Fed a High-Fat Diet12

Consuming a high-fat (HF) diet produces excessive weight gain, adiposity, and metabolic complications associated with risk for developing type 2 diabetes and fatty liver disease. This study evaluated the influence of whey protein isolate (WPI) on systemic energy balance and metabolic changes in mice fed a HF diet. Female C57BL/6J mice received for 11 wk a HF diet, with or without 100 g WPI/L drinking water. Energy consumption and glucose and lipid metabolism were examined. WPI mice had lower rates of body weight gain and percent body fat and greater lean body mass, although energy consumption was unchanged. These results were consistent with WPI mice having higher basal metabolic rates, respiratory quotients, and hepatic mitochondrial respiration. Health implications for WPI were reflected in early biomarkers for fatty liver disease and type 2 diabetes. Livers from WPI mice had significantly fewer hepatic lipid droplet numbers and less deposition of nonpolar lipids. Furthermore, WPI improved glucose tolerance and insulin sensitivity. We conclude that in mice receiving a HF diet, consumption of WPI results in higher basal metabolic rates and altered metabolism of dietary lipids. Because WPI mice had less hepatosteatosis and insulin resistance, WPI dietary supplements may be effective in slowing the development of fatty liver disease and type 2 diabetes