Metabolic Susceptibility of 2-Chlorothioxanthone and Its Toxic Effects on mRNA and Protein Expression and Activities of Human CYP1A2 and CYP3A4 Enzymes

Abstract

Thioxanthones (TXs) are photoinitiators widely used in UV curable resins and food packaging, and their residues have been frequently detected in human bodies. Our current understanding of the susceptibility of residual TXs to metabolism and their effects on human health is very limited. The in vitro metabolism of TXs and its toxic effects on cytochrome P450 (CYP) (the key xenobiotic metabolizing enzymes) were examined in this study. 2-Chlorothioxanthone (2-Cl-TX) significantly inhibited the enzymatic activities of CYP1A2 and CYP3A4 with IC 50 of 8.36 and 0.86 μM, respectively. The exposure to 2-Cl-TX at 2.5 μM up-regulated the mRNA expression of CYP1A2 and CYP3A4 in human hepatocellular carcinoma cells to 3.03-fold and 2.02-fold, respectively. 2-Cl-TX at 2.5 μM caused 2.19-fold and 1.98-fold overexpression of CYP1A2 and CYP3A4, respectively. In vitro studies revealed that 2-Cl-TX was biotransformed into two metabolites through the sulfoxidation of the sulfur atom, or via the hydroxylation of aromatic carbon. Results from this study, including the metabolic susceptibility of residual 2-Cl-TX, the proposed metabolites and the significant toxic effect on the activities, mRNA, and protein expression of CYP1A2 and CYP3A4, are vital to the human health and safety risk assessment from this ubiquitous xenobiotic.

Photoinitiators in Breast Milk from United States Donors: Occurrence and Implications for Exposure in Infants

“…PIs have been reported to have toxic effects, making the presence of PIs in humans and the environment a matter of public and scientific concern. For example, TXs can significantly inhibit the enzymatic activity of human cytochrome P450 . 2-ITX was demonstrated to have antiestrogenic and antiandrogenic effects by yeast-based estrogen and androgen bioassays, , while 2-ethylhexyl-4-(dimethylamino) benzoate (EHDAB) has been shown to have estrogenic and androgenic properties by in vitro bioassays .…”

“…For example, TXs can significantly inhibit the enzymatic activity of human cytochrome P450. 11 2-ITX was demonstrated to have antiestrogenic and antiandrogenic effects by yeast-based estrogen and androgen bioassays, 12,13 while 2-ethylhexyl-4-(dimethylamino) benzoate (EHDAB) has been shown to have estrogenic and androgenic properties by in vitro bioassays. 14 BP and 4,4′-bis(dimethylamino) benzophenone (MK) were identified as potential carcinogens.…”

Gene Expression of Antioxidant Metabolic Enzymes in Grape Extracts

“…The body can also alleviate oxidative stress in vivo by supplementing antioxidants. However, some synthetic antioxidants have shown potential adverse reactions such as liver injury, especially long-term use of synthetic antioxidants (12). Therefore, exploring safe and natural antioxidants to resist oxidative stress has become a research hotspot in recent years (13).…”

Bayesian machine learning to discover Bruton’s tyrosine kinase inhibitors

“…In addition, DB‐VS suffers the problem of inaccurate scoring functions, which often leads to low hit rate and enrichment (Warren et al, 2006). The PB‐VS approach often bears a higher false‐positive rate (Yang, 2010; Yao et al, 2004; Zhan et al, 2018). Machine learning method provides an alternative selection for virtual screening as well as for the prediction of ADMET properties in recent years (Lei et al, 2017; Li et al, 2014; Lv et al, 2017; Wang et al, 2012; Wang et al, 2016; Zhuang et al, 2017).…”