Biotransformation enzyme polymorphism and pesticide susceptibility

Numerous specific genetic polymorphisms (PM) in the multi-gene families of cytochromes P450 (CYPs) and glutathione S-transferases (GSTs) have been described in the human population in the past decade. For example, one or more PM have been identified in human CYP1A1, CYP1B1, CYP2C9, CYP2C18, CYP2D6, and CYP2E1. Recent studies using cDNA expressed human CYPs have suggested that CYP3A4 is the principal human CYP involved in the oxidation of parathion and probably other organo(thio)phosphate (OP) insecticides and thus PM in this CYP might influence susceptibility to OP. However, although large (> 10-fold) variability in CYP3A4 activity in human liver has been found, thus far no genetic basis for differences in activity or expression of CYP3A4 have been identified. Three GSTs are also polymorphic in the human population. Approximately 50% of the Caucasian population are homozygous for a gene deletion of the mu class GSTM1, and approximately 20% of Caucasians and over 60% of certain Asian populations are homozygous for a partial deletion of the theta-class GSTT1. Recently, several single nucleotide polymorphisms in human GSTP1 have also been described, and have altered activity toward several substrates. No studies have yet determined the relative activities of human GSTM1, T1 or PI towards methylparathion or other pesticides, and thus the potential significance of the common polymorphisms of these genes on pesticide susceptibility is unknown. Numerous studies have demonstrated that resistance of a variety of insects to several different insecticides, including DDT, has been attributed to the overexpression of theta-class GSTs as well as certain CYPs. Thus, it remains possible that genetic PM in human GSTs and/or CYP enzymes could increase or decrease sensitivity to certain pesticides. Few epidemiological studies have examined whether any of the known CYP or GST PMs are associated with adverse outcomes in populations occupationally-exposed to pesticides.