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CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition.
Drug Metab Dispos
April 2024
Drug Metabolism, Gilead Sciences Inc., Foster City, California.
Drug-induced liver injury (DILI) is a frequent cause of clinical trial failures during drug development. While inhibiting bile salt export pump (BSEP) is a well-documented DILI mechanism, interference with genes related to bile acid (BA) metabolism and transport can further complicate DILI development. Here, the effects of twenty-eight compounds on genes associated with BA metabolism and transport were evaluated, including those with discontinued development or use, boxed warnings, and clean labels for DILI.
View Article and Find Full Text PDFIn vivo mapping of rat brain partial white matter content using hexachlorophene-induced neurotoxicity model.
Brain Res
May 2024
Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, United States.
Segmentation of the white matter in MRI scans of the rat brain presents a significant challenge due to the low contrast. Existing anatomical reference maps of rat brain are usually constructed from fixed tissue, which may suffer from geometrical distortions due to fixation/processing. To significantly increase the in vivo contrast between white and gray matter in the rat brain we used a known neurotoxicant hexachlorophene, which produces selective white matter damage.
View Article and Find Full Text PDFThe sensitivity of the zebrafish embryo coiling assay for the detection of neurotoxicity by compounds with diverse modes of action.
Environ Sci Pollut Res Int
June 2023
Aquatic Ecology and Toxicology, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 504, 69120, Heidelberg, Germany.
In the aim to determine neurotoxicity, new methods are being validated, including tests and test batteries comprising in vitro and in vivo approaches. Alternative test models such as the zebrafish (Danio rerio) embryo have received increasing attention, with minor modifications of the fish embryo toxicity test (FET; OECD TG 236) as a tool to assess behavioral endpoints related to neurotoxicity during early developmental stages. The spontaneous tail movement assay, also known as coiling assay, assesses the development of random movement into complex behavioral patterns and has proven sensitive to acetylcholine esterase inhibitors at sublethal concentrations.
View Article and Find Full Text PDFHexachlorophene, a selective SHP2 inhibitor, suppresses proliferation and metastasis of KRAS-mutant NSCLC cells by inhibiting RAS/MEK/ERK and PI3K/AKT signaling pathways.
Toxicol Appl Pharmacol
April 2022
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China. Electronic address:
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations account for 35% of the genetic alterations in non-small cell lung cancer (NSCLC). The Src-homology region 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is closely involved in RAS downstream pathways and development of many tumors by affecting cell proliferation, differentiation, and immunity. Targeting SHP2 with small molecules may be a promising avenue for the treatment of KRAS-mutant (mut) NSCLC.
View Article and Find Full Text PDFAssessment of Skin Photoallergy Risk in Cosmetics Containing Herbal Extract Ingredients.
Skin Pharmacol Physiol
January 2022
Department of Dermato-Venereology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Background/objective: In recent years, herbal extracts are becoming increasingly popular ingredients added in cosmetics; however, the assessment of their potential adverse effects on the skin remains unclear. As Coptis, Phellodendron amurense, curcumin, and shikonin are herbs currently used in cosmetic ingredients, the aim of this study was to assess their skin photoallergy (PA) potential and the concentrations at which they could safely be used.
Methods: In the patch test, Coptis, P.
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