Salvinorin A, a potent hallucinogen from Salvia divinorum, is rapidly eliminated after intraperitoneal dosing in rats, with a half-life of 75 minutes and a clearance of 26 L/h/kg. Its distribution is extensive (47.1 L/kg), but brain levels are low (brain-to-plasma ratio 0.050) and the brain half-life is only 36 minutes. In cell studies, salvinorin A is transported by P-glycoprotein and metabolized by several enzymes, including CYP2D6, CYP1A1, CYP2C18, CYP2E1, and UGT2B7. These findings align with the compound's fast onset and short duration of action.
MDMA (ecstasy) causes organ damage partly through increased oxidative and nitrosative stress. This review focuses on how oxidative modifications of mitochondrial proteins lead to mitochondrial dysfunction. It describes a method using biotin-N-maleimide as a sensitive probe to identify oxidatively-modified mitochondrial proteins in rats exposed to MDMA, and discusses applications and limitations of this Cys-targeted proteomics approach. The review also covers synergistic drug interactions between MDMA and alcohol, and the potential of this redox-based proteomics method for developing preventive and therapeutic agents against MDMA-induced organ damage.
MDMA (ecstasy) causes liver damage, but the mechanism was poorly understood. In rats, MDMA exposure led to abnormal liver histology, elevated plasma transaminases, nitric oxide synthase, and hydrogen peroxide. Oxidatively modified mitochondrial proteins were labeled with a sensitive probe and identified via mass spectrometry. These included proteins involved in energy supply, fat metabolism, antioxidant defense, and chaperone activities. The activities of mitochondrial aldehyde dehydrogenase, 3-ketoacyl-CoA thiolases, and ATP synthase were significantly inhibited. The data show that MDMA causes oxidative inactivation of key mitochondrial enzymes, likely contributing to mitochondrial dysfunction and subsequent liver damage.