The approved drug thalidomide is teratogenic in humans, nonhuman primates, and rabbits but not in rodents. The extensive biotransformation of 5′-hydroxythalidomide after oral administration of thalidomide (250 mg/kg) in rats was investigated in detail using liquid chromatography–tandem mass spectrometry. Probable metabolites 5′-hydroxythalidomide sulfate and glucuronide were extensively formed, with approximately tenfold and onefold peak areas, respectively, to the primary 5′-hydroxythalidomide measured using authentic standards. As a minor metabolite, 5-hydroxythalidomide was also detected. The output of simplified physiologically based pharmacokinetic rat models was consistent with the observed in vivo data under a metabolic ratio of 0.05 for the hepatic intrinsic clearance of thalidomide to unconjugated 5′-hydroxythalidomide. The aggregate of unconjugated and sulfate/glucuronide conjugated 5′-hydroxythalidomide forms appear to be the predominant metabolites in rats. Two hours after oral administration of thalidomide (100 mg/kg) to chimeric mice humanized with four different batches of genotyped human hepatocytes, the plasma concentration ratios of 5-hydroxythalidomide to 5′-hydroxythalidomide were correlated with replacement indexes of human liver cells previously transplanted in immunodeficient mice. These results indicate that rodent livers mediate thalidomide primary oxidation, leading to extensive deactivation in vivo to unconjugated/conjugated 5′-hydroxythalidomide and suggest that thalidomide activation might be dependent on the humanized livers in mice transplanted with human hepatocytes.
Cadmium is an environmental toxic metal and its exposure has become a worldwide public health threat. We aimed to evaluate the exposure assessment of cadmium in people living in Ta Zin Yae Kyaw village of Nyaung Don Township in Ayeyarwady Division, Myanmar and adverse effects of cadmium on the kidneys. Subjects (18-40 years) residing in this village were selected as the exposed group (n = 65) and those living in Kamayut Township in Yangon Division, Myanmar as the control group (n = 65). Spot urine samples were taken for determination of urinary cadmium concentration using graphite-furnace atomic absorption spectrometry (GFAAS) method and adjusted to the concentration of creatinine in urine. To assess the kidney function, urinary β2-microglobulin level was determined by ELISA, serum creatinine was measured by colorimetric Jaffe method and estimated glomerular filtration rate (eGFR) was calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Urine cadmium concentrations were significantly higher in the exposed group (median (Interquartile range): 0.96 (0.19-1.77) μg/g Creatinine) compared to the control (p = 0.036). Urinary β2-microglobulin levels were significantly higher (p = 0.000) and eGFR was significantly lower in the exposed group (p = 0.013) compared to the control. In addition, urine cadmium level showed significant positive correlation with urinary β2-microglobulin in all study population (p < 0.01). Positive correlation becomes stronger (p < 0.01) in the exposed group only. For eGFR, significant negative correlation was found in all study population (p < 0.01) and exposed group (p < 0.01). Our findings suggested that environmental cadmium exposure can induce renal dysfunction in both tubular and glomerular functions in apparently healthy human adults.
Lidocaine has been shown to inhibit the invasion and metastasis of breast cancer, but the mechanism still remains unclear. This study explored the relationship between lidocaine and circulating seeding of breast cancer cells from the perspective of nerve fiber formation. The cell lines MDA-MB-231 and 4T1 were subcutaneously inoculated in mice to simulate the tumor self-seeding by circulating cancer cells. Lidocaine was used to treat these mice and tumor growth was observed. Silver staining was performed to observe the distribution of nerve fibers in tumor-bearing tissues, and immunohistochemical analysis was performed to observe the expression levels of nerve-related proteins. The results showed that lidocaine treatment effectively inhibited tumor growth and nerve fiber formation, and down-regulated the expression levels of protein gene product 9.5, neurofilament, nerve growth factor (NGF), and neuronatin (Nnat). Overexpression NGF and Nnat both could reverse the therapeutic effects of lidocaine. These results suggest that the effect of lidocaine on inhibiting breast cancer invasion and metastasis may be achieved by targeting Nnat, regulating the production of NGFs in cancer cells, and subsequently inhibiting the formation of nerve fibers.
Reactive sulfur species (RSS) include biological persulfide molecules that protect cells against oxidative stress and heavy metal toxicity. Vascular endothelial cells regulate blood coagulation and fibrinolytic activity, and prevent vascular disorders such as atherosclerosis. We hypothesized that RSS protect vascular endothelial cells not only from nonspecific cell damage but also from specific functional damage through regulation of specific cell functions. In the present study, cultured bovine aortic endothelial cells were treated with sodium trisulfide, a sulfane sulfur donor, and both [3H]thymidine incorporation and effects on cell cycle were analyzed. These results suggest that RSS stimulate vascular endothelial cell proliferation. RSS may reduce the functional cytotoxicity of antiproliferative agents.