Toxicoproteomics reveals an effect of Clozapine on autophagy in human liver spheroids

ABSTRACT: Clozapine is an atypical antipsychotic drug for treatment-resistant schizophrenia. Its side effects, including liver enzyme abnormalities, experienced by many patients preclude a more common use as a first-line therapy of schizophrenia. Toxicoproteomics approaches have been demonstrated to effectively guide the identification of toxicological mechanisms. Here, to further our understanding of Clozapine's molecular effects we performed a Data-independent Acquisition (DIA)-based quantitative proteomics investigation of Clozapine-treated human liver spheroid cultures. In total, we quantified 4,479 proteins across five treatment groups (vehicle, 15 µM, 30 µM, 60 µM Clozapine, and 10 ng/mL TNFa + IL-1a). 60 µM Clozapine treatment yielded 36 differentially expressed proteins (fdr < 0.05). Gene-set enrichment analysis indicated perturbation of several gene-sets, which included interferon gamma signaling (e.g., IFNGR1) and prominently autophagy related processes (e.g., upregulation of SQSTM1, MAP1LC3B/LC3B2, GABARAPL2, and NCOA4). Clozapine's effects on autophagy were confirmed using conventional SQSTM1 and LC3B markers by targeted mass-spectrometry and Western Blot.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Liver

SUBMITTER: Bjoern Titz  

LAB HEAD: Bjoern Titz

PROVIDER: PXD034257 | Pride | 2022-12-09

REPOSITORIES: Pride