Archives of Toxicology最新文献

Psilocin is a well-studied controlled substance with potential psychotherapeutic applications. However, research gaps remain regarding its metabolism. Our objective was to elucidate a comprehensive Phase I metabolic profile of psilocin to support its forensic management and clinical development. We utilized human enzymes from various sources to characterize the Phase I metabolism of psilocin and estimated its hepatic and extrahepatic clearances via in vitro to in vivo extrapolation. We identified 2-(4-hydroxy-1H-indol-3-yl)-acetaldehyde (4-HIA) as the Phase I intermediate metabolite for the first time. Psilocin was metabolized to 4-HIA by monoamine oxidase A (MAO-A), and further metabolized to the terminal metabolite 2-(4-hydroxy-1H-indol-3-yl)-acetic acid (4-HIAA) by cytosolic aldehyde oxidase (AO) and aldehyde dehydrogenases (ALDHs). MAO-A-mediated hepatic clearance of psilocin (CL_H,MAO-A) was estimated to be 158.74 mL/min, accounting for 80.9% of the total hepatic metabolism of psilocin (CL_H,all). MAO-A primarily contributed to the Phase I metabolism of psilocin. Total MAO-A-mediated organ clearance (CL_{all organs,MAO-A}) was estimated to be 614.81 mL/min, with CL_H,MAO-A accounting for 25.8%, indicating extensive MAO-A-mediated extrahepatic clearance of psilocin. Overall, our study sheds novel insights on Phase I metabolic pathway of psilocin and illuminated the importance of MAO-A-mediated hepatic and extrahepatic clearances of psilocin.

The tumorigenic dose 50 (TD₅₀) is a widely used measure of carcinogenic potency which has historically been used to determine acceptable intake limits for carcinogenic compounds. Although broadly used, the TD₅₀ model was not designed to account for important biological factors such as DNA repair and cell compensatory mechanisms, changes in absorption, etc., leading to the development of benchmark dose (BMD) approaches, which use more flexible dose-response models that are better able to account for these processes. Using a nitrosamine dataset as a case study, we compare the impact of moving to a BMD-based limit as opposed to a TD₅₀-based limit. Although there are differences in individual potency estimates between the two approaches for some compounds, we show that the key metrics such as the 5^th percentile of the respective potency distributions, used when calculating class-specific default acceptable intakes, are not greatly affected. Furthermore, potency estimates for nitrosamine compounds relevant to read-across do not vary by more than a factor of 3, which is little in the context of the inherent variability in a biological response, in an overall landscape wherein potencies can vary by four orders of magnitude. This suggests a move to BMD-based limits is achievable without significant disruption to existing limits while utilising a more robust methodology.

Systemic bile acid homeostasis plays an important role in human health. In this study, a physiologically based kinetic (PBK) model that includes microbial bile acid deconjugation and intestinal bile acid reuptake via the apical sodium-dependent bile acid transporter (ASBT) was applied to predict the systemic plasma bile acid concentrations in human upon oral treatment with the antibiotic tobramycin. Tobramycin was previously shown to inhibit intestinal deconjugation and reuptake of bile acids and to affect bile acid homeostasis upon oral exposure of rats. Kinetic parameters to define the effects of tobramycin on intestinal bile acid transport were determined in vitro using a Caco-2 cell layer Transwell model for studying the intestinal translocation of 4 model bile acids including glycochenodeoxycholic acid (GCDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and deoxycholic acid (DCA), the latter as a model for unconjugated bile acids (uBA). Kinetic constants for the effect of tobramycin on intestinal microbial deconjugation were taken from previous in vitro studies using anaerobic fecal incubations. The PBK model simulations predicted that exposure to tobramycin at the dose level also used in the previous 28 day rat study would reduce human plasma C_max levels of GCA, GCDCA, GDCA, and DCA by 42.4%, 27.7%, 16.9%, and 75.8%. The reduction of conjugated bile acids is governed especially via an effect on ASBT-mediated intestinal uptake, and not via the effect of tobramycin on intestinal conjugation, likely because deconjugation happens to a large extent in the colon which has limited subsequent bile acid reuptake. The results reflect that oral exposure to xenobiotics that are not or poorly bioavailable can affect systemic bile acid homeostasis. Altogether, the PBK model appears to provide a 3R compliant tool to evaluate the effect of oral exposure to xenobiotics on host bile acid homeostasis via effects on intestinal bile acid deconjugation and reuptake.

Chemotherapy, a cornerstone of cancer treatment, is frequently marred by its hepatotoxic effects, which can significantly impede therapeutic efficacy. This systematic review meticulously evaluates the hepatoprotective properties of phytochemicals and plant extracts against chemotherapy-induced liver damage, primarily in experimental animal models. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, an exhaustive search was conducted across databases like SCOPUS, PubMed, and Web of Science, culminating in the inclusion of 61 pertinent studies. These studies illustrate those natural compounds, spanning a diverse array of phytochemicals and plant extracts that can effectively mitigate biochemical markers of liver damage, enhance antioxidant defences, and modulate inflammatory responses in model organisms subjected to hepatotoxic chemotherapeutic agents such as cyclophosphamide, cisplatin, and doxorubicin. Notably, the natural agents reviewed have demonstrated significant reductions in liver enzymes, improved histopathological outcomes, and bolstered cellular antioxidant capacities. The systematic synthesis of data underscores the potential of these natural substances to diminish liver toxicity associated with chemotherapy in preclinical settings. However, the review also highlights critical gaps in research, notably the underreporting of molecular mechanisms and inconsistent data on clinical translatability. To optimize the therapeutic utility of these compounds, future studies should focus on detailed molecular analyses and rigorous clinical trials to validate efficacy and safety, paving the way for integrated approaches in oncological care that minimize hepatic complications.

Depleted uranium (DU) is a byproduct of uranium enrichment, which can cause heavy-metal toxicity and radiation toxicity as well as serious damage to the kidneys. However, the mechanism of renal injury induced by DU is still unclear. This study aimed to explore the role of ethylmalonic encephalopathy 1 (ETHE1) in DU-induced mitochondrial dysfunction and elucidate the underlying mechanisms. Using ETHE1 gene knockout C57BL/6 mice (10 mg/kg DU) and renal cell models (500 µM DU) exposed to DU, we observed significantly reduced levels of hydrogen sulfide (H₂S) and glutathione (GSH), alongside decreased adenosine triphosphate (ATP) content and increased oxidative stress. Our results demonstrated that knocking out or silencing ETHE1 led to a significant reduction in H₂S and GSH levels, whereas the opposite occurred when was ETHE1 overexpressed. When the H₂S donor sodium hydrosulfide and GSH precursor N-acetylcysteine were used to treat animals or cells, cellular ATP levels were increased, oxidative stress markers were reduced, and kidney damage was mitigated. In addition, H₂S and GSH interacted with each other after DU poisoning. These findings suggest that the ETHE1/H₂S/GSH pathway plays a critical role in mediating DU-induced mitochondrial dysfunction in renal cells, highlighting potential therapeutic targets for mitigating the harmful effects of DU. Thus, this study expands our understanding of DU-induced renal damage pathways, providing avenues for further research and intervention strategies.

The constant emergence of new viral pathogens underscores the need for continually evolving, effective antiviral drugs. A key challenge is identifying compounds that are both efficacious and safe, as many candidates fail during development due to unforeseen toxicity. To address this, the embryonic zebrafish morphology, mortality, and behavior (ZBE) screen and the SYSTEMETRIC® Cell Health Screen (CHS) were employed to evaluate the safety of 403 compounds from the Cayman Antiviral Screening Library. Of these compounds, 114 were FDA-approved, 17 were discontinued, and 97 remained on the market. CHS identified 25% (104 compounds) as toxic, with a Cell Health Index™ (CHI) > 0.5. The embryonic zebrafish model identified an additional 20% as toxic (79), bringing the total to 183. ZBEscreen flagged 19 toxic hits among compounds still on the market, seven of which were also identified by CHS. The combined use of CHS and zebrafish models enhanced hazard detection. Together, CHS and ZBEscreen identified 45.5% of the library as potentially hazardous. Notably, the zebrafish non-hazardous compounds correlated strongly with over-the-counter or prescribed antiviral drugs, confirming their known safety profile. Over 130 hazard-associated compounds warranted further investigation. Using self-organizing maps, six distinct neighborhoods of compound similarity were identified. This dual approach streamlined the early detection of hazards associated with promising leads and is expected to facilitate faster, safer antiviral discovery.

In daily life, individuals are frequently exposed to various forms of radiation, which, when adhering to safety standards, typically result in relatively minor health effects. However, accidental exposure to radiation levels that exceed these safety standards can lead to significant health consequences. This study focuses on the analysis of radiation-induced damage to the nervous system and the mechanisms of pharmacological protection. The findings indicate that radiation can adversely affect neural structures, memory, and neurobehaviour. A range of pharmacological agents, including traditional Chinese medicine, Western medicine, and other therapeutic drugs, can be employed to safeguard the nervous system from radiation damage. The primary protective mechanisms of these agents encompass antioxidant effects, attenuation of apoptosis, and reduction of neurogenesis. A comprehensive review of these topics will offer new insights for the development and investigation of drugs aimed at mitigating radiation-induced damage to the nervous system.