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

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...

Full description

Saved in:
Bibliographic Details
Published in:Environmental science & technology 2018-10, Vol.52 (20), p.11904-11912, Article acs.est.8b04643
Main Authors: Zhan, Tingjie, Pan, Liumeng, Liu, Zhenfeng, Chen, Jiayan, Ge, Zhiwei, Lu, Liping, Zhang, Xiaofang, Cui, Shixuan, Zhang, Chunlong, Liu, Weiping, Zhuang, Shulin
Format: Article
Language:English
Subjects:
CYP1A2 protein
Cytochrome
Cytochrome P450
Cytochromes P450
Enzymatic activity
Enzymes
Food packaging
Gene expression
Health risks
Hepatocellular carcinoma
Hydroxylation
Metabolism
Metabolites
Photoinitiators
Protein expression
Proteins
Resins
Risk assessment
Sulfoxidation
Sulfur
Toxicity
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 IC50 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.
ISSN:0013-936X
1520-5851
DOI:10.1021/acs.est.8b04643