The Polymerization Agent, 2-Methyl-4′-(methylthio)-2-morpholinopropiophenone Induces Caspases-3/7 in Human Blood Mononuclear Cells <i>in Vitro</i>

Abstract

Our previous studies detected the presence of a photoinitiator 2-methyl-4′-(methylthio)-2-morpholinopropiophenone (MTMP) in an intravenous (i.v.) injection bag solution. Importantly, MTMP has demonstrated cytotoxicity for normal human peripheral blood (PB) mononuclear cells (MNC). Cell death pathways have two well-known modes, apoptosis and necrosis. But it has not been clear whether MTMP induced apoptosis or necrosis in normal human PB MNC. In the present in vitro study, we examined normal human PB MNC for the frequencies of apoptosis and necrosis and changes upon exposure to MTMP. We observed time-dependent changes in MNC viability with MTMP. We also assessed the activity of caspases-3/7. The results demonstrated that MTMP induced apoptosis in normal human PB MNC after 24 h. In addition, MTMP induced caspases-3/7 in a time-dependent manner. In conclusion, we suggest that MTMP induces apoptosis in a caspase-dependent pathway in vitro.Key words photoinitiator; apoptosis; caspase-3; caspase-7; cytotoxicity; human mononuclear cell Photoinitiators are used in a broad range of commercial and biological applications such as printing, 1) dentistry, 2) encapsulation of pancreatic islet cells, 3,4) and blood vessel adhesives.5) Thus, a high level of daily exposure to photoinitiators is possible. In previous in vitro studies, it was reported that photopolymerizing agents were cytotoxic. The photoinitiators Sarcat CD 1012, Araidite GY 281 and Epon 825 were cytotoxic to L929 cells, 6) and 4-octylphenyl phenyliodoniumhexafluoroantimonate (OPIA) also was severely cytotoxic.7) In other studies, Irgacure 2959 was found to be the least toxic photoinitiator while 1-hydroxycyclohexyl phenyl ketone (Irgacure 184) and 2,2-dimethoxy-2-phenylacetophenone (Irgacure 651) were significantly more toxic to human fetal osteoblasts. 8)In our recent study, we detected the presence of the photoinitiator 2-methyl-4′-(methylthio)-2-morpholinopropiophenone (MTMP) at approximately 2.8 mg/bag (5.6 µg/mL) in an intravenous (i.v.) injection bag solution. We demonstrated that MTMP was cytotoxic to normal human peripheral blood (PB) mononuclear cells (MNC). 9)

First Detection of Photoinitiators and Metabolites in Human Sera from United States Donors

“…28 A follow-up study found cytotoxicity of PI-907 for human peripheral blood mononuclear cells. 29 2-Benzyl-2-(dimethylamino)-4′-morpholinobutyrophenone (PI-369), which has a similar structure to PI-907, was detected at much lower concentrations (<MQL− 879 pg/mL; GM: 1.68 pg/mL) and frequency (8%). The possible reasons of lower detection of PI-369 (lgK ow = 4.50) in the serum samples might include its limited use and/or higher predicted hydrophobicity compared to PI-907 (logK ow = 2.73) (Table S1).…”

“…One previously identified exposure pathway of PI-907 was via intravenous injection bag solutions . A follow-up study found cytotoxicity of PI-907 for human peripheral blood mononuclear cells . 2-Benzyl-2-(dimethylamino)-4′-morpholinobutyrophenone (PI-369), which has a similar structure to PI-907, was detected at much lower concentrations (<MQL–879 pg/mL; GM: 1.68 pg/mL) and frequency (8%).…”

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

“…This activity caused by EHDAB was also observed in human estrogen receptor α (hERα) and hERβ stably transfected HEK293 cells . However, an in vivo study based on uterotrophic assay and transgenic zebrafish assay did not detect the estrogenic activity of EHDAB. , Conversely, PI-907 can induce apoptosis of human peripheral blood mononuclear cells by activating caspases-3/7 . Exposure to PI-907 considerably reduced cell viability according to the MTT assay .…”

“…126,127 Conversely, PI-907 can induce apoptosis of human peripheral blood mononuclear cells by activating caspases-3/7. 128 Exposure to PI-907 considerably reduced cell viability according to the MTT assay. 73 Additionally, DEAB exposure substantially increased the percentage of slightly damaged HL-60 cells, as measured by the comet assay and trypan blue dye exclusion, indicating its DNA-damaging activity.…”

Three photoinitiators induce breast tumor growth in mouse xenografts with MCF-7 breast cancer cells

“…However, the pharmacokinetics of MTMP have yet to be elucidated in detail. We showed that MTMP induced apoptosis through a caspase-dependent pathway via caspase-3/7 in vitro ( Kawasaki et al, 2013 ). Moreover, 1-HCHPK, MBB, and MTMP did not exhibit mutagenicity in the Ames test.…”