Cytotoxic effects of thioxanthone derivatives as photoinitiators on isolated rat hepatocytes

Abstract

Thioxanthone and its analogues, 2-or 4-isopropylthioxanthone, 2-chlorothioxanthone, 2,4-diethylthioxanthone (DETX) and xanthone, are used as photoinitiators of ultraviolet (UV) light-initiated curable inks. As these photoinitiators were found in numerous food/beverage products packaged in cartons printed with UV-cured inks, the cytotoxic effects and mechanisms of these compounds were studied in freshly isolated rat hepatocytes. The toxicity of DETX was greater than that of other compounds. DETX elicited not only concentration (0-2.0 mM)-and time (0-3 hours)-dependent cell death accompanied by the depletion of cellular adenosine triphosphate (ATP), and reduced glutathione (GSH) and protein thiol levels, but also the accumulation of GSH disulfide and malondialdehyde. Pretreatment of hepatocytes with either fructose at a concentration of 10 mM or N-acet yl-L-cysteine (NAC) at a concentration of 5.0 mM ameliorated DETX (1 mM)-induced cytotoxicity. Further, the exposure of hepatocytes to DETX resulted in the induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential, both of which were partially prevented by the addition of NAC. These results indicate that: (1) DETX-induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were, at least in part, ameliorated by the addition of fructose; and (3) GSH loss and/or ROS formation was prevented by NAC. Taken collectively, these results suggest that the onset of toxic effects caused by DETX may be partially attributable to cellular energy stress as well as oxidative stress.The exposure of rat hepatocytes to thioxanthone photoinitiators, especially 2,4diethylthioxanthone (DETX), caused cell death accompanied by the depletion of intracellular ATP and glutathione, and the induction of glutathione disulfide, all of which were partially prevented by the preincubation with N-acetyl-L-cysteine (NAC) or fructose. DETXinduced cytotoxicity was also associated by mitochondrial dysfunction and reactive oxygen species formation, which could be prevented by NAC. These results suggest that DETXinduced cytotoxicity may be attributable to cellular energy stress and/or oxidative stress.

Occurrence, Fate, Human Exposure, and Toxicity of Commercial Photoinitiators

“…In addition, the increased ROS generation and decreased mitochondrial membrane potential suggest that the cytotoxicity of DETX may result from cellular energy stress and/or oxidative stress. 122 6.3. Amine Co-Initiators.…”

“…In freshly isolated rat hepatocytes, DETX is more toxic than TX, 2-ITX, and 2-Cl-ITX on cell death. In addition, the increased ROS generation and decreased mitochondrial membrane potential suggest that the cytotoxicity of DETX may result from cellular energy stress and/or oxidative stress …”