Conformational changes in proteins in vitro as a means of predicting the acute toxicities of chemicals.
Experimental data are presented on ovalbumin denaturation (OD, EC10) and human acetylcholine esterase (AChE) inhibition (IC50) in vitro, following exposure to the chemicals used in the international Multicentre Evaluation of In vitro Cytotoxicity (MEIC) programme. Data were obtained for 40 (OD test) and 43 (AChE test) of the 50 MEIC chemicals. These data were compared with similar data from other methods used in the MEIC programme, and good correlations (R2) were obtained with data from MEIC studies on cell lines: 0.80 for human, 0.81 for other animal, and 0.78 for fish cell line IC50 values and AChE values, and 0.76 for human, 0.69 other animal and 0.75 for fish cell line IC50 values and OD values. The correlation increased substantially, if chemicals which freely cross the blood-brain barrier were solely considered, with R2 = 0.90 for human, 0.90 for other animal, and 0.82 for fish cell line IC50 values and AchE values, and 0.87 for human, 0.86 for other animal, and 0.92 for fish cell line IC50 values and OD values, in this case. Such chemicals are the main cause of non-specific depression of the central nervous system (CNS). The AChE IC50 permits a good prediction of human acute toxicity, similar to the IC50 values obtained with human cell lines and the same MEIC chemicals. These results confirm the basal toxicity hypothesis formulated by Björn Ekwall. It is concluded that in vitro methods based on the disruption of the functions of the proteins vital for body operation can be used as an alternative to the cell culture methods, when non-specific toxic effects of chemicals on humans and animals are evaluated.
Loukianov
Anatoly S
AS
M.V. Lomonosov Moscow State University, Department of Biology, Moscow, Russia. asloukianov@mail.ru
Syomina
Tatiana K
TK
Korolev
Aleksander M
AM
D000110:Acetylcholinesterase / Q000187:drug effects; D000826:Animal Testing Alternatives; D000818:Animals; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D010047:Ovalbumin / Q000737:chemistry* / Q000187:drug effects*; D011237:Predictive Value of Tests; D011487:Protein Conformation / Q000187:drug effects*; D023382:Toxicity Tests, Acute / Q000379:methods*; D015262:Xenobiotics / Q000633:toxicity*
D002800:Cholinesterase Inhibitors; D015262:Xenobiotics; D010047:Ovalbumin; D000110:Acetylcholinesterase