ABSTRACT
OBJECTIVE To compare the species difference of T-2 toxin metabolism in liver micro-somes of different animals. METHODS T-2 toxin was incubated with liver microsomes from mice, rats,Beagle dogs, monkeys and humans, respectively, at 37℃ for some time. Then, the incubation liquid was detected by high liquid chromatography-mass spectrometry method after albumen precipitation. RESULTS The half-life (t1/2) of T-2 toxin was less than 1 min, 2-4 min in mouse and monkey liver microsomes, 13 min in dog liver microsomes, and 39 min in rat liver microsomes. The hepatic clear-ance (Clh) of T-2 toxin was divided into three groups among the five species of animals:humans, dogs and rats were in one group, monkeys a second group, and mice in another group. The Clh of mouse group was 3-4 times that of the human, dog and rat group. The affinity to T-2 toxin was different between the liver microsomes of these five species. The affinity of mouse liver microsomes was the strongest, followed by that of humans, dogs, rats and monkeys. The enzyme transfer rate of T-2 toxin was the highest in monkey liver microsomes followed by that of rats and dogs. It was one million times higher in monkey liver microsomes than in human and mouse liver microsomes. The major metabolites were 3′-hydroxyl-T-2 toxin and neosolaniol. T-2 triol and HT-2 toxins were the major metabolites in human and rat liver microsomes. HT-2 toxin and 3′-OH-T-2 toxin were the dominating metabolites in dog liver microsomes and T-2 triol and 3′-OH-T-2 toxin in mouse liver microsomes. T-2 toxin metabolited by hydrolysis effect in mouse, rat, dog and human liver microsomes, but through hydroxylation in monkey liver microsomes. CONCLUSION There are species differences in metabolic parameters, metabolites, amounts of metabolites, metabolic pathways of T-2 toxin in mouse, rat, dog, monkey and human liver microsomes.
ABSTRACT
Objective To investigate the toxic effects and mechanisms of sulphur mustard on DNA damage of human immortalized epidermal keratinocytes (HacaT cells).Methods The inhibitory effect of sulphur mustard on the proliferation of HacaT cells was detected by CCK-8 method.The apoptosis index of cells was measured by Annexin V-FITC method.The effects of sulphur mustard on DNA damage were detected by single cell gel electrophoresis.The expression levels of DNA damage and repair related proteins were detected by Western blot.Results The proliferation rate of HacaT cells was inhibited in a dose-dependent manner after treatment with sulphur mustard for 24 h (IC50 value was 121 mol/L).The apoptotic and comet tailing rates of cells treated with sulphur mustard also increased in a dose-dependent manner.The expression levels of DNA damage and repair related proteins were changed after treatment with sulphur mustard.Conclusion Sulphur mustard has significant cytotoxic effect on HacaT cells,and can induce apoptosis and DNA damage.In addition,ATM-P53-γH2AX-PARP signaling pathway plays an important role in the repair of DNA damage induced by sulphur mustard.