Two CES1 Gene Mutations Lead to Dysfunctional Carboxylesterase 1 Activity in Man: Clinical Significance and Molecular Basis

Abstract

The human carboxylesterase 1 (CES1) gene encodes for the enzyme carboxylesterase 1, a serine esterase governing both metabolic deactivation and activation of numerous therapeutic agents. During the course of a study of the pharmacokinetics of the methyl ester racemic psychostimulant methylphenidate, profoundly elevated methylphenidate plasma concentrations, unprecedented distortions in isomer disposition, and increases in hemodynamic measures were observed in a subject of European descent. These observations led to a focused study of the subject's CES1 gene. DNA sequencing detected two coding region single-nucleotide mutations located in exons 4 and 6. The mutation in exon 4 is located in codon 143 and leads to a nonconservative substitution, p.Gly143Glu. A deletion in exon 6 at codon 260 results in a frameshift mutation, p.Asp260fs, altering residues 260-299 before truncating at a premature stop codon. The minor allele frequency of p.Gly143Glu was determined to be 3.7%, 4.3%, 2.0%, and 0% in white, black, Hispanic, and Asian populations, respectively. Of 925 individual DNA samples examined, none carried the p.Asp260fs, indicating it is an extremely rare mutation. In vitro functional studies demonstrated the catalytic functions of both p.Gly143Glu and p.Asp260fs are substantially impaired, resulting in a complete loss of hydrolytic activity toward methylphenidate. When a more sensitive esterase substrate, p-nitrophenyl acetate was utilized, only 21.4% and 0.6% catalytic efficiency (V(max)/K(m)) were determined in p.Gly143Glu and p.Asp260fs, respectively, compared to the wild-type enzyme. These findings indicate that specific CES1 gene variants can lead to clinically significant alterations in pharmacokinetics and drug response of carboxylesterase 1 substrates.

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

“…Rare nonsynonymous variants in CES1 encode enzymes with impaired activities that dramatically alter the pharmacokinetics and drug response to the psychostimulant methylphenidate. 45 Several CES2 variants have been shown to be functionally deficient, and some have decreased esterase activities toward the anticancer agent irinotecan. 46 CES are clearly important in a variety of pharmacogenetic phenotypes.…”

Genetic Polymorphisms of theCarboxylesterase 1(CES1) Gene in a Korean Population

“…[2,8] Although their functional consequences remain uncertain, several CES1 variants have been reported in NCBI SNP database. The CES1 allele and estimated haplotype frequencies showed significant differences between African and European populations.…”

“…[2,6,7] In-vitro functional studies have demonstrated that the G143E and the D260fs variants have reduced catalytic function, resulting in the disruption of hydrolytic activity of CES1. [8,9] In a single-dose pharmacokinetic study, these two CES1 mutations were identified in one subject who displayed 7-fold higher total methylphenidate (i.e., combined d-and l-isomers) concentrations compared to that of other subjects (n=19). [2,9] In addition, -75T>G polymorphism was associated with the reduced appetite in attention deficit-hyperactivity disorder (ADHD) youths treated with methylphenidate [10] and the isoniazid-induced hepatotoxicity in latent tuberculosis infection patients.…”

Hallusinosis due to methylphenidate overdose in an eight-year-old child: a case report

“…The monitorization study which is conducted by positron emission tomography (PET) revealed that dopaminergic changes in brain may have huge personal variety [18]. Because of polymorphism of carboxylesterase 1 enzyme which metabolize MPH primarily, MPH rises to unexpected high doses [17,19]. Although it is not clearly denoted as psychosis, another group which is prone to stimulants' adverse effects is the group who has neurodevelopmental disorders like mental retardation and autism [13].…”