Age‐ and Gender‐Dependent In Vitro Hepatic Metabolism and acute neurotoxicity of a pyrethroid insecticide, Deltamethrin (DLM), in Rats

Metabolism is a critical determinant of DLM acute neurotoxicity as the parent compound is the toxic moiety. The aim of this study was to determine whether age- and gender-related differences in DLM metabolism by CYP450s and/or carboxylesterases (CaEs) exist and dictate the susceptibility to the chemical. Metabolism was quantified in vitro by monitoring disappearance of the parent compound from liver microsomes (via CaEs and CYP450s) obtained from 21- and 90-d-old male and female S-D rats. Intrinsic clearances (Vmax/Km) by CaEs (male−1.8±0.4 and 12.01±1.1; female−2.3±0.4 and 7.2±1.0) and CYP450s (male−16.9±1.9 and 35.5±2.9; female−10.7±2.3 and 19.7±5.4) increased with age in both sexes due to marked increases in Vmax and slight increases in Km. While there was no gender difference in young rats, intrinsic clearance of DLM by both pathways was significantly higher in adult males than that of females. CYP450s played a more important role than CaEs in DLM metabolism in rats of both sexes and ages. Preliminary results of in vivo experiments showed that young male and female rats receiving 10 mg/kg po showed severe toxic signs and 100% mortality. Male and female adult rats receiving 10 or 20 mg/kg DLM showed only mild to moderate toxicity. A gender difference was not evident at 10 mg/kg, but females showed more pronounced toxic signs and higher blood and brain DLM levels at 20 mg/kg. This study shows that limited metabolic capacity contributes to the age- and gender-dependent differences in sensitivity to acute DLM neurotoxicity. Gender dependency, however, was evident only in adults. (Supported by EPA STAR Grant R830800).