Mimicking of Phase I Metabolism Reactions of Molindone by HLM and Photocatalytic Methods with the Use of UHPLC-MS/MS.

Establishing the metabolism pathway of the drug undergoing the hepatic biotransformation pathway is one of the most important aspects in the preclinical discovery process since the presence of toxic or reactive metabolites may result in drug withdrawal from the market. In this study, we present the structural elucidation of six, not described yet, metabolites of an antipsychotic molecule: molindone. The elucidation of metabolites was supported with a novel photocatalytical approach with the use of WO3 and WS2 assisted photochemical reactions. An UHPLC-ESI-Q-TOF combined system was used for the registration of all obtained metabolite profiles as well as to record the high resolution fragmentation spectra of the observed transformation products. As a reference in the in vitro metabolism simulation method, the incubation with human liver microsomes was used. Chemometric comparison of the obtained profiles pointed out the use of the WO3 approach as being more convenient in the field of drug metabolism studies. Moreover, the photocatalysis was used in the direction of the main drug metabolite synthesis in order to further isolation and characterization.

Roles of Sulfur Metabolism and Rhodanese in Detoxification and Anti-Oxidative Stress Functions in the Liver: Responses to Radiation Exposure.

Organisms must confront various environmental stresses. The liver is central to protecting against such stresses in mammals, and it has many detoxification and anti-oxidative stress functions. Radiation is a source of oxidative stress and is known to affect the liver and induce anti-oxidative responses. The detoxification enzyme rhodanese, which is also called thiosulfate sulfurtransferase (TST), has been demonstrated to be induced in the liver in response to radiation. Cyanide detoxification is a function of the liver, and rhodanese is a key enzyme involved in sulfur metabolism in that detoxification. Though the anti-oxidative stress system in which sulfur molecules such as thiol compounds are involved has attracted attention as a defense against radiation, detoxification enzymes may have other roles in this defense. Understanding how these functions are affected by alterations of sulfur metabolism (including thiol compounds) after irradiation would help uncover their roles in defense against cancer and other deleterious health effects, as well as environmental stress responses. This article reviews the roles of sulfur-related metabolism in oxidative stress regulation and detoxification for recovery from liver damage after radiation exposure, with particular attention to recent findings of sulfur-related enzymes such as rhodanese, which is unique in sulfur metabolism.