FURTHER ASSESSMENT OF AN<i>IN VITRO</i>SCREEN THAT MAY HELP IDENTIFY ORGANOPHOSPHORUS PESTICIDES THAT ARE MORE ACUTELY TOXIC TO THE YOUNG

Padilla, Stephanie; Sung, Ha‐Jung; Moser, Virginia C.

doi:10.1080/15287390490483836

Cited by 29 publications

(20 citation statements)

References 43 publications

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“…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).…”

Section: Downloaded Frommentioning

confidence: 99%

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

Zhu

Markowitz

2008

Drug Metab Dispos

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ABSTRACT:Oseltamivir phosphate is an ethyl ester prodrug widely used in the treatment and prevention of both Influenzavirus A and B infections. The conversion of oseltamivir to its active metabolite oseltamivir carboxylate is dependent on ester hydrolysis mediated by carboxylesterase 1 (CES1). We recently identified two functional CES1 variants p.Gly143Glu and p.Asp260fs in a research subject who displayed significant impairment in his ability to metabolize the selective CES1 substrate, methylphenidate. In vitro functional studies demonstrated that the presence of either of the two mutations can result in severe reductions in the catalytic efficiency of CES1 toward methylphenidate, which is required for hydrolysis and pharmacological deactivation. The aim of the present study was to investigate the function of these mutations on activating (hydrolyzing) oseltamivir to oseltamivir carboxylate using the cell lines expressing wild type (WT) and each mutant CES1. In vitro incubation studies demonstrated that the S9 fractions prepared from the cells transfected with WT CES1 and human liver tissues rapidly convert oseltamivir to oseltamivir carboxylate. However, the catalytic activity of the mutant hydrolases was dramatically hindered. The V max value of p.Gly143Glu was approximately 25% of that of WT enzyme, whereas the catalytic activity of p.Asp260fs was negligible. These results suggest that the therapeutic efficacy of oseltamivir could be compromised in treated patients expressing either functional CES1 mutation. Furthermore, the potential for increased adverse effects or toxicity as a result of exposure to high concentrations of the nonhydrolyzed prodrug should be considered.Oseltamivir phosphate (Tamiflu; Roche, Nutley, NJ) is widely used in the treatment and prophylaxis of both Influenzavirus A and B infections. In addition, oseltamivir may be effective in preventing or treating avian influenza or so-called "bird flu." Oseltamivir is an ester prodrug and, in general, it is readily converted to its active form oseltamivir carboxylate mediated by hepatic carboxylesterase 1 (CES1) (Fig. 1) . The active metabolite exerts its antiviral effects via the selective inhibition of neuraminidase.Carboxylesterases are members of the ␣␤ hydrolase -fold family and expressed in many tissues, especially in the liver, small intestine, and lung (Satoh and Hosokawa, 2006;Ross and Crow, 2007). The major human carboxylesterases include CES1 (UniProtKB/Swiss-Prot P23141) and carboxylesterase 2 (CES2) (UniProtKB/Swiss-Prot O00748). CES1 and CES2 are largely distinguished from one another by their substrate specificity and tissue distribution (Imai et al., 2006;Satoh and Hosokawa, 2006). CES1 more readily catalyzes substrates with a relatively large acyl group and small alcohol group such as methylphenidate, temocapril, and oseltamivir (Sun et al., 2004;Imai et al., 2005;Shi et al., 2006). In contrast, CES2 preferentially hydrolyzes compounds bearing a small acyl moiety and bulky alcohol group, which includes agents such as cocaine a...

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Section: Downloaded Frommentioning

confidence: 99%

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

Zhu

Markowitz

2008

Drug Metab Dispos

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“…Using in vitro tests, measurements of esterase (carbarylesterase, A-esterase) detoxification have also revealed good concordance between juvenile sensitivity and degree of esterase detoxification (Moser and Padilla, 2011;Padilla et al 2000Padilla et al , 2004. Extrapolation of these findings suggest that the chemicals most dependent on esterases for detoxification will be more toxic to the young, and that screening for this can be predictive of juvenile sensitivity.…”

Section: Kineticsmentioning

confidence: 97%

“…2002Karanth and Pope 2000;Mortensen et al 1996;. In addition to chlorpyrifos, esterase detoxification, determined in vivo and/or in vitro, is known to be important for diazinon, mevinphos, malathion, and propoxur (e.g., Cashman et al 1996;Murphy 1971, 1974;Gupta and Dettbarn 1993;Gupta and Kadel 1990;Main and Braid 1962;Moser and Padilla, 2011;Padilla et al 2000Padilla et al , 2004Poet et al 2003;Walker and Mackness 1987). These chemicals all showed ≥3-fold increased sensitivity in the www.intechopen.com…”

Section: Kineticsmentioning

confidence: 99%

Age-Related Differences in Acetylcholinesterase Inhibition Produced by Organophosphorus and N-Methyl Carbamate Pesticides

Moser¹

2011

Pesticides in the Modern World - Pests Control and Pesticides Exposure and Toxicity Assessment

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“…Young animals are far more susceptible than adults to organophosphate-induced growth inhibition and lethality, there is a wide range over which disparate compounds elicit such effects. For example, parathion is far more systemically toxic to newborn rats than is chlorpyrifos, in part reflecting pharmacokinetic differences centering around the ontogeny of enzymes activating the parent compounds to the corresponding oxons, compared with the enzymes that break down the oxons to inactive metabolites (Atterberry et al 1997;Padilla et al 2000Padilla et al , 2004. The maximum tolerated doses of each agent correspond closely to the relative potencies toward cholinesterase inhibition and to the rate of recovery of cholinesterase activity, thus drawing a direct mechanistic connection of cholinergic hyperstimulation to overall systemic toxicity (Pope and Chakraborti 1992;Pope et al 1991;Tang et al 2003).…”

Section: Developmental Toxicitymentioning

confidence: 99%

Chronic Exposure to Pesticides- Neurological, Neurobehavioral and Molecular Targets of Neurotoxicity

B.K¹,

Gill²

2011

Pesticides in the Modern World - Effects of Pesticides Exposure

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FURTHER ASSESSMENT OF ANIN VITROSCREEN THAT MAY HELP IDENTIFY ORGANOPHOSPHORUS PESTICIDES THAT ARE MORE ACUTELY TOXIC TO THE YOUNG

Cited by 29 publications

References 43 publications

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

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

Age-Related Differences in Acetylcholinesterase Inhibition Produced by Organophosphorus and N-Methyl Carbamate Pesticides

Chronic Exposure to Pesticides- Neurological, Neurobehavioral and Molecular Targets of Neurotoxicity

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