Carboxylesterase and A-Esterase Activities during Maturation and Aging: Relationship to the Toxicity of Chlorpyrifos and Parathion in Rats

Abstract

Chlorpyrifos (CPF) and parathion (PS), two common organophosphorus (OP) pesticides, exhibit higher acute toxicity in younger animals compared to adults. Maturational differences in detoxification via carboxylesterases (CEs) and A-esterases (AEs) have been suggested as contributors to the higher sensitivity of younger animals to OP toxicants. AEs (e.g., chlorpyrifos oxonase and paraoxonase) catalytically inactivate while CEs stoichiometrically eliminate OP anticholinesterases. While earlier studies have reported a relationship between the toxicity of some OP pesticides and the maturational profile of AEs and CEs, little information exists on the relative OP-toxicant sensitivity and detoxification capacities of aged animals. In the present study, we investigated the relationship between toxicity of CPF and PS and the activity of CEs and AEs in liver, plasma, and lung of neonatal (7 day), juvenile (21-day), adult (3-month), and aged (24-month) Sprague Dawley rats. CE sensitivity in vitro to chlopyrifos oxon and paraoxon was also evaluated across age groups. Neonatal and juvenile rats were more sensitive than adults to the acute lethality of both CPF and PS. Aged rats exhibited similar sensitivity to CPF but were markedly more sensitive than adults to PS. Levels of CEs and AEs in neonatal and juvenile rats were significantly lower than in adult tissues. Aged rats showed similar levels of AEs in all tissues and CEs in liver and lung, but plasma CE levels were significantly lower (50%) when compared to the adult rats. There were no significant age-related differences in in vitro sensitivity of CEs to either chlorpyrifos oxon or paraoxon in any tissues. In general, acute sensitivity (MTD) was highly correlated with age-related differences in both esterase activities across all 3 tissues with CPF, but only plasma carboxylesterase activity was highly correlated with sensitivity to parathion. The results suggest that both carboxylesterase and A-esterase activities can be correlated with acute sensitivity to CPF and PS, but that age-related differences in CE activity are probably more important in differential toxicity. Furthermore, plasma carboxylesterase activity may play a more pivotal role in the differential sensitivity to PS.

Chlorpyrifos Induced Region Specific Vulnerability in Rat CNS and Modulation by Age and Cold Stress: An Interactive Study

“…The maturing animals viz., neonates and juveniles are more susceptible to acute toxic effects of CPF than young adults, primarily because of lower levels of detoxifying enzymes. The detoxification of CPF include binding to carboxylesterases and hydrolysis by arylesterases [26] and these mechanisms appear to have got altered differentially in different age group of rats since physiologic systems differ in different age group leading to homeostatic alterations, as a result the ability to respond adequately to toxic stress or insult varies. Young animals are unique because of the immature nervous system which responds differentially to the exposure of CPF with its kinetic ability (absorption, distribution, metabolism & excretion).…”

Activation of the Antiviral Prodrug Oseltamivir Is Impaired by Two Newly Identified Carboxylesterase 1 Variants

“…Converging evidence suggests that CES1 function in juvenile animals remain at a significantly lower level than that of adult animals (Kadner et al, 1992;Morgan et al, 1994;Moser et al, 1998;Karanth and Pope, 2000;Padilla et al, 2004;Anand et al, 2006). Animal studies demonstrated that juvenile rats did not hydrolyze oseltamivir efficiently, and they are more susceptible than adults to oseltamivir toxicity (http://www.fda.gov/cder/ foi/nda/2000/21-246_Tamiflu_Pharmr.pdf).…”

Distinct Patterns of Aging Effects on the Expression and Activity of Carboxylesterases in Rat Liver and Intestine

“…PNPA hydrolysis also decreased with age (Table 2), due presumably to downregulation of CES1 isozyme levels, although CESs are responsible for only 65% of the total hepatic microsomal hydrolysis of PNPA. Karanth and Pope (2000) reported that the hydrolase activity for PNPA was identical at 90 days (13 weeks) and 24 months (96 weeks) in the hepatic S9 fraction of Sprague-Dawley rats. In the present experiments, we used hepatic microsomal fractions from Wistar rats.…”

“…In the same rats, the hepatic intrinsic clearance of the pyrethroid deltamethrin, through oxidation by cytochrome P450 (P450), reaches maximum activity in 40-day-old rats. Karanth and Pope (2000) reported that hepatic activity against p-nitrophenyl acetate (PNPA) increases with age in rats and reaches maximum activity at 90 days, maintaining this level of activity up to 24 months, while maximal activity in plasma is reached at 90 days and has decreased by 24 months.…”