3.3. Potentiation of OPs toxicity b

3.3. Potentiation of OPs toxicity by organochlorine insecticides
The CYP450 family of enzymes is important for both the acti- vation and detoxification of OPs. The relative rates at which organophosphorothioates (OPTs) insecticides are activated and detoxified may be an important determinant of toxicity. Indepen- dently of the chemical structure, bioactivation of OPTs such as malathion, chlorpyrifos, diazinon, azynphos-methyl and parathion to the very highly toxic oxon forms is carried out by the same CYP450 systems (Buratti et al., 2005). These insecticides feature a thio-phosphate moiety that is subjected to oxidative desulfu- ration in which the CYP450s remove the sulfur atom attached to the phosphorus and insert atomic oxygen (Fig. 4). This results in covalent binding of sulfur to CYP, a reaction that occurs prefer- entially at cysteine residues leading to an irreversible inactivation of the enzymes that catalyze the reactions. This mechanism- based inhibition of CYP450 is a suicide reaction for the P450 carrying out the reaction (Hodgson and Rose, 2007; Kyle et al.,
2012).
At low OPT concentration, oxon derivatives formation is mainly catalyzed by CYP1A2 and to a lesser extent by CYP2B6, whereas CYP3A4 is relevant only at high OPT levels (Buratti et al., 2005). Individuals with low CYP2C19 activity, responsible for the oxida- tive cleavage of OPT, but high CYP1A2 and CYP2B6 activities might be more susceptible to OPT toxicity (Hodgson and Rose,
2007). Given that organochlorine pesticides, such as endosulfan- ␣, are CYP3A4 inducers, previous or concurrent utilization of these compounds can potentiate OPs toxicity (Casabar et al., 2006), par- ticularly when the OPs occur at high concentrations (see Fig. 4). DDT is also able to induce CYP2B and CYP3A in rat liver (Smith,
2011).
3.4. Potentiation of carbaryl toxicity by OPs
An increased sensitivity to the NMC pesticide carbaryl fol- lowing pretreatment with malathion or chlorpyrifos has been attributed to the OPT-induced suicide inhibition of CYP450 ulti- mately resulting in inhibition of carbaryl metabolism (Hodgson and Rose,2007; Johnston,1995).CYP1A2 has the greatest ability to form 5-hydroxycarbaryl, while CYP3A4 is the most active in generation of 4-hydroxycarbaryl (Fig. 5). The production of carbaryl methy- lol is primarily the result of metabolism by CYP2B6 (Tang et al.,
2002). Therefore, the suicide reaction of the CYP450s involved in the oxidative desulfuration of OPT insecticides will prevent car- baryl from being detoxified, remaining only the hydrolysis step catalyzed by esterases yielding ␣-naphtol. However,such esterases can be inhibited by the oxon generated in the desufuration step and thus any pathway of carbaryl metabolism is completely blocked, leading to a potentiation effect beyond the expected additive anti- cholinesterase effect (Fig. 5).