The Long Term Changes in Liver DNA and Total Protein Contents Following Low Level Sarin Exposure in Rats

Abstract

1. The changes in contents of DNA and total protein in the liver of the rats exposed to low level sarin by inhalation at 3, 6 and 12 months following the exposure were studied. The influence of sarin on the DNA and protein metabolism in liver was determinated by the measurements of incorporation of tritiated thymidine into DNA, the concentration of DNA and total protein. 2. Our results show that not only symptomatic level 3 but also asymptomatic levels 1 and 2 of sarin are able to significantly decrease the incorporation of radiolabelled thymidine without changing total concentrations of DNA as well as protein at three months following sarin exposure. On the other hand, the significant decrease in total contents of DNA and protein in liver without the changes in the incorporation of tritiated thymidine was determined in liver six months following sarin exposure. Practically no significant changes in the metabolism of DNA and protein were observed at 12 months following sarin exposure. 3. Thus, not only clinically manifested intoxication but also low-level, asymptomatic exposure to nerve agents such as sarin is able to influence the metabolism of nucleic acids as well as proteins even several months following the exposure.

The Influence of Acetylcholinesterase Reactivators on Selected Hepatic Functions in Rats

“…However, the factual effect of decreased expression of Mrp2 protein on hepatocellular excretory function remains unclear. Decreased expression of Mrp2 after administration of K027, HI‐6 and obidoxime may play an important role in hepatocellular injury due to accumulation of toxic materials in liver cells and may enhance the hepatocellular toxicity of organophosphate intoxication [2,3]. On the contrary, several studies have observed increased compensatory expression of multidrug resistance protein 3 (Mrp3), another transporter organic anions and member of multidrug resistance protein family, as a result of increased levels of blood bilirubin and bilirubin glucuronides [25,26].…”

“…observed liver dysfunction and hepatotoxicity following obidoxime administration to patients during the Iraq–Iran war [1]. Moreover, the hepatotoxic effect of oxime treatment may aggravate the hepatotoxic effect of organophosphate intoxication [2,3]. Therefore, the choice of oximes for the treatment of organophosphate poisoning is rather complex.…”

The Influence of Acetylcholinesterase Reactivators on Selected Hepatic Functions in Rats

“…However, the factual effect of decreased expression of Mrp2 protein on hepatocellular excretory function remains unclear. Decreased expression of Mrp2 after administration of K027, HI‐6 and obidoxime may play an important role in hepatocellular injury due to accumulation of toxic materials in liver cells and may enhance the hepatocellular toxicity of organophosphate intoxication [2,3]. On the contrary, several studies have observed increased compensatory expression of multidrug resistance protein 3 (Mrp3), another transporter organic anions and member of multidrug resistance protein family, as a result of increased levels of blood bilirubin and bilirubin glucuronides [25,26].…”

“…observed liver dysfunction and hepatotoxicity following obidoxime administration to patients during the Iraq–Iran war [1]. Moreover, the hepatotoxic effect of oxime treatment may aggravate the hepatotoxic effect of organophosphate intoxication [2,3]. Therefore, the choice of oximes for the treatment of organophosphate poisoning is rather complex.…”

The evaluation of oxidative damage of DNA after poisoning with nerve agents

“…OPC have many non-specific effects involving the activation of multiple non-cholinergic neurotransmitter systems in the central nervous system, mutagenic, stressogenic, immunotoxic, hepatotoxic, membrane and hematotoxic effects (Bajgar, 2004). OPC-induced glutamate-mediated excitotoxicity (O'Donnell et al, 2011), calcium overload (Choi, 1988), ATP depletion and cellular energy loss (Gupta et al, 2001), alteration of immune functions (Kassa et al, 2000a) and DNA damage (Kassa et al, 2000b;Mehta et al, 2008;Ojha et al, 2013) were also described in the literature. The non-specific effects of OPC are considered to contribute to their long-term toxic effects, therefore, it is important to find the mechanism of the non-specific effects of OPC at the cellular and molecular level.…”

Soman and VX: different effect on cellular signalling

“…The basic mechanism of their toxicity is well known and lies in irreversible binding to and inactivation of acetylcholinesterase (AChE, EC 3.1.1.7), which is associated with the accumulation of acetylcholine at the synapses and overstimulation of the cholinergic nervous system (Marrs 1993). By contrast, less is known about nerve agent-induced non-specific effects including the influence on non-cholinergic neurotransmitter levels and especially oxidative stress interfering with cellular DNA metabolism and resulting in organophosphate genotoxicity and mutagenicity (Kassa et al 2000, Klaidman et al 2003, Bajgar 2004 (Pazdernik et al 2001, Klaidman et al 2003. Therefore, finding the mechanisms of nerve agent-induced non-specific effects might contribute to early diagnosis and complex treatment of nerve agent poisoning.…”

The Influence of Acetylcholinesterase Reactivators on Selected Hepatic Functions in Rats

“…However, the factual effect of decreased expression of Mrp2 protein on hepatocellular excretory function remains unclear. Decreased expression of Mrp2 after administration of K027, HI‐6 and obidoxime may play an important role in hepatocellular injury due to accumulation of toxic materials in liver cells and may enhance the hepatocellular toxicity of organophosphate intoxication [2,3]. On the contrary, several studies have observed increased compensatory expression of multidrug resistance protein 3 (Mrp3), another transporter organic anions and member of multidrug resistance protein family, as a result of increased levels of blood bilirubin and bilirubin glucuronides [25,26].…”

“…observed liver dysfunction and hepatotoxicity following obidoxime administration to patients during the Iraq–Iran war [1]. Moreover, the hepatotoxic effect of oxime treatment may aggravate the hepatotoxic effect of organophosphate intoxication [2,3]. Therefore, the choice of oximes for the treatment of organophosphate poisoning is rather complex.…”

The evaluation of oxidative damage of DNA after poisoning with nerve agents

“…OPC have many non-specific effects involving the activation of multiple non-cholinergic neurotransmitter systems in the central nervous system, mutagenic, stressogenic, immunotoxic, hepatotoxic, membrane and hematotoxic effects (Bajgar, 2004). OPC-induced glutamate-mediated excitotoxicity (O'Donnell et al, 2011), calcium overload (Choi, 1988), ATP depletion and cellular energy loss (Gupta et al, 2001), alteration of immune functions (Kassa et al, 2000a) and DNA damage (Kassa et al, 2000b;Mehta et al, 2008;Ojha et al, 2013) were also described in the literature. The non-specific effects of OPC are considered to contribute to their long-term toxic effects, therefore, it is important to find the mechanism of the non-specific effects of OPC at the cellular and molecular level.…”

Soman and VX: different effect on cellular signalling

“…The basic mechanism of their toxicity is well known and lies in irreversible binding to and inactivation of acetylcholinesterase (AChE, EC 3.1.1.7), which is associated with the accumulation of acetylcholine at the synapses and overstimulation of the cholinergic nervous system (Marrs 1993). By contrast, less is known about nerve agent-induced non-specific effects including the influence on non-cholinergic neurotransmitter levels and especially oxidative stress interfering with cellular DNA metabolism and resulting in organophosphate genotoxicity and mutagenicity (Kassa et al 2000, Klaidman et al 2003, Bajgar 2004 (Pazdernik et al 2001, Klaidman et al 2003. Therefore, finding the mechanisms of nerve agent-induced non-specific effects might contribute to early diagnosis and complex treatment of nerve agent poisoning.…”

The Influence of Acetylcholinesterase Reactivators on Selected Hepatic Functions in Rats

“…However, the factual effect of decreased expression of Mrp2 protein on hepatocellular excretory function remains unclear. Decreased expression of Mrp2 after administration of K027, HI‐6 and obidoxime may play an important role in hepatocellular injury due to accumulation of toxic materials in liver cells and may enhance the hepatocellular toxicity of organophosphate intoxication [2,3]. On the contrary, several studies have observed increased compensatory expression of multidrug resistance protein 3 (Mrp3), another transporter organic anions and member of multidrug resistance protein family, as a result of increased levels of blood bilirubin and bilirubin glucuronides [25,26].…”

“…observed liver dysfunction and hepatotoxicity following obidoxime administration to patients during the Iraq–Iran war [1]. Moreover, the hepatotoxic effect of oxime treatment may aggravate the hepatotoxic effect of organophosphate intoxication [2,3]. Therefore, the choice of oximes for the treatment of organophosphate poisoning is rather complex.…”

The evaluation of oxidative damage of DNA after poisoning with nerve agents

“…OPC have many non-specific effects involving the activation of multiple non-cholinergic neurotransmitter systems in the central nervous system, mutagenic, stressogenic, immunotoxic, hepatotoxic, membrane and hematotoxic effects (Bajgar, 2004). OPC-induced glutamate-mediated excitotoxicity (O'Donnell et al, 2011), calcium overload (Choi, 1988), ATP depletion and cellular energy loss (Gupta et al, 2001), alteration of immune functions (Kassa et al, 2000a) and DNA damage (Kassa et al, 2000b;Mehta et al, 2008;Ojha et al, 2013) were also described in the literature. The non-specific effects of OPC are considered to contribute to their long-term toxic effects, therefore, it is important to find the mechanism of the non-specific effects of OPC at the cellular and molecular level.…”

Soman and VX: different effect on cellular signalling

“…The basic mechanism of their toxicity is well known and lies in irreversible binding to and inactivation of acetylcholinesterase (AChE, EC 3.1.1.7), which is associated with the accumulation of acetylcholine at the synapses and overstimulation of the cholinergic nervous system (Marrs 1993). By contrast, less is known about nerve agent-induced non-specific effects including the influence on non-cholinergic neurotransmitter levels and especially oxidative stress interfering with cellular DNA metabolism and resulting in organophosphate genotoxicity and mutagenicity (Kassa et al 2000, Klaidman et al 2003, Bajgar 2004 (Pazdernik et al 2001, Klaidman et al 2003. Therefore, finding the mechanisms of nerve agent-induced non-specific effects might contribute to early diagnosis and complex treatment of nerve agent poisoning.…”