Short chain chlorinated paraffins (SCCPs) are emerging persistent organic pollutants of great concern due to their ubiquitous distribution in the environment. However, little information is available on the biotransformation of SCCPs in organisms. In this study, a chlorinated decane: 1, 2, 5, 5, 6, 9, 10-heptachlorodecanes (HeptaCDs) was subjected to in vitro metabolism by human and chicken liver microsomes at environmentally relevant concentration. Using ultra-performance liquid chromatography-Q-Exactive Orbitrap mass spectrometry, two metabolites: monohydroxylated hexachlorodecane (HO-HexCD) and monohydroxy heptachlorodecane (HO-HeptaCD) were detected in human liver microsomal assays, while only one metabolite (HO-HexCD) was identified in chicken liver microsomal assays. The formation of HO-HexCD was fitted to a Michaelis-Menten model for chicken liver microsomes with a V (maximum metabolic rate) value of 4.52 pmol/mg/min. Metabolic kinetic parameters could not be obtained for human liver microsomes as steady state conditions were not reached under our experimental conditions. Notwithstanding this, the observed average biotransformation rate of HeptaCDs was much faster for human liver microsomes than for chicken liver microsomes. Due to the lack of authentic standards for the identified metabolites, the detailed structure of each metabolite could not be confirmed due to the possibility of conformational isomers. This study provides first insights into the biotransformation of SCCPs, providing potential biomarkers and enhancing understanding of bioaccumulation studies.
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http://dx.doi.org/10.1016/j.scitotenv.2022.158261 | DOI Listing |
Eur J Drug Metab Pharmacokinet
December 2024
Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Objective: The objective of this study was to determine the apparent intrinsic clearance (Cl) and fraction unbound in human liver microsomes (f) of 86 marketed central nervous system (CNS) drugs and to predict the in vivo hepatic blood clearance (CL).
Methods: Cl in human liver microsomes (HLM) was determined by substrate depletion, and f was determined by equilibrium dialysis. The relationship between lipophilicity (logP) and unbound intrinsic clearance (Cl) was explored using the Biopharmaceutical Drug Disposition Classification System (BDDCS) and Extended Clearance Classification System (ECCS).
Basic Clin Pharmacol Toxicol
January 2025
Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.
The worldwide legalization of medicinal cannabis has led to an increased use of products made by commercial operators. These products often contain minor cannabinoids such as cannabinol (CBN) which are advertised to improve sleep. Products are also available in which CBN is combined with conventional therapies, with a common product containing both CBN and the widely used sleep-aid melatonin.
View Article and Find Full Text PDFEur J Med Chem
December 2024
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China. Electronic address:
Targeting the biosynthetic pathway of mycolic acid is highly attractive to researchers in the field of novel anti-tubercular drug development. Pks13-TE is an essential catalytic component in the last assembling step of mycolic acid, and the co-crystal structures of the Pks13-TE-inhibitor complex provide insight into ligand recognition. Based on a structure-guided strategy, N-aryl indole derivatives were designed, synthesized, and evaluated for their antitubercular activities.
View Article and Find Full Text PDFEur J Med Chem
December 2024
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, 63110, USA; Center for Clinical Pharmacology, Washington University School of Medicine and University of Health Sciences and Pharmacy, St. Louis, Missouri, 63110, USA; Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, Missouri, 63110, USA. Electronic address:
Inhibition of mitochondrial pyruvate transport via the mitochondrial pyruvate carrier (MPC) has shown beneficial effects in treating metabolic diseases, certain cancers, various forms of neurodegeneration, and hair loss. These benefits arise either from the direct inhibition of mitochondrial pyruvate metabolism or from the metabolic rewiring when pyruvate entry is inhibited. However, current MPC inhibitors are either nonspecific or possess poor pharmacokinetic properties.
View Article and Find Full Text PDFZhongguo Zhong Yao Za Zhi
October 2024
State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine Tianjin 301617, China Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine Tianjin 301617, China.
UDP-glucuronosyltransferases(UGTs) are the main phase Ⅱ metabolizing enzymes in the human body, participating in the glucuronidation of various chemicals in the body. Traditional Chinese medicine(TCM) ingredients affect the activities of UGTs involved in drug metabolism, and the fluctuations in the blood concentrations of drugs metabolized by UGTs will lead to the risk of TCM-TCM or TCM-chemical drug interaction, which will cause drug safety problems and affect drug efficacy. Therefore, it is essential to explore the effect of TCM ingredients on the activities of UGTs.
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