Experiments on the theory of photochemical formation of carcinogens from skin fats.
Irradiation products of skin surface fats, including digitonin-precipitable sterols, isocholesterols, and total unsaponifiable fractions, were painted on the ears of white mice for periods of from 15 to 18 months, but failed to produce precancerous or cancerous changes that could be noted histologically. Therefore, the theory of photochemical formation of carcinogenic compounds on the surface of the skin by ultraviolet irradiation could not be substantiated by this method.
Arsenic trioxide induces ROS activity and DNA damage, leading to G0/G1 extension in skin fibroblasts through the ATM-ATR-associated Chk pathway
Arsenic (As) toxicity is a global health problem, affecting millions of people. Exposure to arsenic, mostly via drinking water, has been associated with cancer of skin, lungs, and blood, in addition to several kinds of skin lesions. The present study focused on the effect of arsenic trioxide (As2O3) on normal skin fibroblast cells. Specifically, the effect of As2O3 on ROS generation and oxidative stress was investigated. Proteins involved in the DNA damage signaling pathway and cell cycle were also studied. As2O3 induced the generation of intracellular ROS. Immunohistochemistry analysis revealed a dose-dependent increase in the number of 8-OHdG-positive cells, an indication of oxidative stress. Cell cycle analysis by flow cytometry demonstrated that As2O3 caused a significant percentage of cells to accumulate in the G0/G1 phase with a concomitant reduction in the S phase. Increases in the activated forms of DNA damage signaling proteins, ATM and ATR, and their effector molecules, Chk2 and p53, were also observed. In addition, expression of oncogene p21 was also increased. The study shows that exposure of normal skin fibroblast cells to As2O3 could lead to cell cycle arrest through ATM/ATR and DNA damage signaling pathways. In conclusion, we report here that arsenic trioxide increases cellular oxidative stress leading to shift in cell cycle and leads to DNA damage through ATM/ATR and the CHK-dependent signaling pathway.
Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteers.
The pharmacokinetics of moxisylyte in plasma and urine was investigated after oral administration. Twelve subjects were treated orally, twice daily with 240 mg of the drug for 6 days; on day 7, the subjects received a last dose of 240 mg of moxisylyte. Moxisylyte was assayed in plasma and urine by a specific HPLC method with fluorimetric detection. Moxisylyte was absorbed rapidly and changed to its metabolites immediately after drug administration; unchanged moxisylyte was not found in plasma. Two metabolites were found in plasma and urine: conjugated desacetylmoxisylyte (DAM) and the conjugate of desmethylated DAM (MDAM). The pharmacokinetic parameters determined after the first oral administration were not modified on multiple dosing. The apparent elimination half-lives of conjugated DAM and MDAM were 2.3 and 3.5 h, respectively. Elimination of these two metabolites in urine averaged 50 and 10%, respectively.