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AGE-DEPENDENT HEAPATIC AND PLASMA METABOLISM OF DELTAMETHRIN IN VITRO: ROLE IN ACUTE NEUROTOXICITY.
Citation:
ANAND, S. S., K. KIM, S. MURALIDHARA, H. J. KIM, J. W. FISHER, J. V. BRUCKNER, AND S. J. PADILLA. AGE-DEPENDENT HEAPATIC AND PLASMA METABOLISM OF DELTAMETHRIN IN VITRO: ROLE IN ACUTE NEUROTOXICITY. Presented at Society of Toxicology, San Diego, CA, March 05 - 09, 2006.
Description:
Deltamethrin (DLM) is a relatively potent and a widely used pyrethroid insecticide. Inefficient metabolism is proposed to be the reason for the greater sensitivity of immature rats to DLM acute neurotoxicity. The aim of this study was to test this hypothesis by characterizing the age-dependency of DLM metabolism, toxic signs, and blood levels of DLM. Metabolism was quantified in vitro by monitoring the disappearance of DLM from plasma [carboxylesterases (CaEs)] and liver (CaEs and CYP450s) obtained from 10-, 21- and 40-d-old male SD rats. Intrinsic clearances (ICs, Vmax/Km) by liver CYP450s (PND10 = 4.99±0.32, 21 = 16.99±1.85 and 40 = 38.45±7.03) and by liver (PND10 = 0.34±0.05, 21 = 1.77±0.38 and 40 = 2.53±0.19) and plasma CaEs (PND10 = 0.39±0.06, 21 = 0.80±0.09 and 40 = 2.28±0.56) increased with age and were attributable to progressive increases in Vmax, as Km did not change. IC of DLM by plasma CaEs and liver CYP450s reached adult levels by 40 d, but IC by liver CaEs did not. ICs by plasma and liver CaEs were comparable at each stage of maturation, but liver CaEs of adult rats exhibited higher IC than plasma CaEs (Anand et al., 2005). Hepatic CYP450s played a more prominant role in DLM biotransformation than CaEs in both young and adults. The severity of neurotoxic effects varied inversely with age when the rats received equivalent dose of DLM (10 mg/kg). Sustained toxic signs resulted in 100% mortality in PND10 and 21, whereas PND40 and 90 experienced only transient salivation and all the rats survived. Correspondingly, blood DLM AUCs of 0-6h progressively decreased with increasing age (PND10 = 12.3, 21 = 6.0, 40 = 3.5 and 90 = 1.9). This study provides evidence that preweanling rats’ limited metabolic capacity contributes to elevated systemic exposure and ensuing adverse effects of DLM. (Supported by EPA STAR Grant R830800). This is an abstract of a proposed presentation and does not necessarily reflect Agency policy.