A kinetic analysis of hepatic microsomal activation of parathion and chlorpyrifos in control and phenobarbital‐treated rats

Abstract

A kinetic analysis of cytochrome P450-mediated desulfuration (activation) or dearylation (detoxication) showed that rat hepatic microsomes have a greater capacity to detoxify and a lower capacity to activate chlorpyrifos compared to parathion. Kinetic curves for the desulfuration of both parathion and chlorpyrifos were biphasic; Kmapps of 0.23 and 71.3 microM were calculated for parathion, and 1.64 and 50.4 microM for chlorpyrifos. While phenobarbital (PB) exposure seemed to generally lower the Kmapps for desulfuration except for the low Km activity on chlorpyrifos, the results were not statistically significant. While the low Km activity contributed 44 and 60% of the control Vmax for parathion and chlorpyrifos, respectively, it contributed 50 and 17% in PB-treated rats. These studies have indicated the presence of a low Km activity capable of functioning at very low substrate concentrations. A single dearylation Kmapp was calculated, 56.0 and 9.8 microM for parathion and chlorpyrifos, respectively. Phenobarbital exposure seemed to raise the Kmapps of dearylation; however, again, the results were not statistically significant. While numerous biochemical factors contribute to the overall toxicity levels of phosphorothionate insecticides, the in vitro efficiencies of hepatic microsomal desulfuration and dearylation of parathion and chlorpyrifos correspond to the acute toxicity levels.

A comparison of the effects of single and repeated exposure to an organophosphate insecticide on acetylcholinesterase activity in mammals

“…Quantification of CYP activity provided some insights regarding the mechanistic interactions between dimethoate and AChE activity. The CYP isoforms CYP1A and CYP2B are involved in the bioactivation of some OPs [22,32‐34]. Exposure of mice to dimethoate did not alter CYP1A1/A2 activity in the present study, which is consistent with findings elsewhere [35].…”

“…The oxons are then ultimately metabolized to the inhibitory forms (through dearylation reactions) by the same CYP enzymes [23]. The balance between the two reaction types may affect the level of AChE inhibition [23] and be a main factor determining toxicity [22]; both reaction types may be ongoing in animals that have experienced multiple exposure events. We therefore also measured the hepatic CYP activities in our experimental animals to determine if CYP activity explained any effect that exposure pattern had on AChE inhibition.…”

Differential acetylcholinesterase inhibition of chlorpyrifos, diazinon and parathion in larval zebrafish

“…From our studies, at the non-lethal concentration of 300nM the efficiency of inhibiting AChE for the 3 compounds was CPF > PA, DZN. While we cannot tell from this study why there is a difference in the molar effectiveness among the OPs, there could be several possible explanations: i) a different efficiency in forming the OP-oxon form for each OP (Buratti et al 2003; Ma and Chambers 1994, 1995; Sams et al 2000); ii) a difference in how effective each OP is at entering the different developmental compartments of the developing embryo; or iii) a difference in the effectiveness of each OP–oxon form at inhibiting AChE (Katz et al 1997). For further discussion we refer the reader to the discussion section of Yang et al (2011).…”

Effects of model organophosphorous pesticides on DNA damage and proliferation of HepG2 cells

“…PT belongs to the phosphorothionates (P5S), which are currently among the most frequently used pesticides [Heudorf et al, 2006]. Phosphorothionates have minimal anti-AChE activity and have to be activated by liver cytochrome P450-mediated oxidative desulphuration to anti-AChE active oxono (P5O) analogs [Ma and Chembers, 1995]. DF was chosen because of its structural similarity to warfare agents.…”