Received for publication October 11, 2005.
Revised November 30, 2005.
Accepted for publication November 30, 2005.

ONTOGENY OF HEPATIC AND PLASMA METABOLISM OF DELTAMETHRIN IN VITRO: ROLE IN AGE-DEPENDENT ACUTE NEUROTOXICITY

Abstract

Deltamethrin (DLM) is a relatively potent and widely used pyrethroid insecticide. Inefficient detoxification has been proposed to be the primary reason for the greater sensitivity of immature rats to DLM acute neurotoxicity. The objective of this study was to test this hypothesis by characterizing the age-dependency of DLM metabolism in vitro, as well as toxic signs and blood levels of the neurotoxic parent compound following administration of 10 mg DLM/kg po in glycerol formal. Metabolism was quantified in vitro by monitoring disappearance of the parent compound from plasma [via carboxylesterases (CaEs)] and liver microsomes [via CaEs and cytochome P450s (CYPs)] obtained from 10-, 21- and 40-d-old (PND) male Sprague-Dawley rats. Mean (±SE) intrinsic clearances (V_max/K_m) in these respective age-groups by liver CYPs (4.99±0.32, 16.99±1.85 and 38.45±7.03) and by liver CaEs (0.34±0.05, 1.77±0.38 and 2.53±0.19) and plasma CaEs (0.39±0.06, 0.80±0.09 and 2.28±0.56) increased significantly (p0.05) with age, due to progressive increases in V_max. Intrinsic clearance of DLM by plasma CaEs and liver CYPs reached adult levels by 40 d, but clearance by liver CaEs did not. Hepatic CYPs played the predominant role in DLM biotransformation in young and adults. The incidence and severity of neurotoxic effects varied inversely with age. Correspondingly, blood DLM AUCs and Cmaxs progressively decreased with increasing age. Internal exposure to DLM (blood AUCs) was closely correlated with toxic signs (salivation and tremors). The present study provides evidence that immature rats' limited metabolic capacity contributes to elevated systemic exposure and ensuing neurotoxic effects of DLM.

Key words: carboxylesterases, cytochrome P450, developmental toxicology, enzyme kinetics, insecticides

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