UNASSIGNED: Carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are among the most abundant hydrolases in humans, catalyzing the metabolism of numerous clinically important medications, such as methylphenidate and clopidogrel. The large interindividual variability in the expression and activity of CES1 and CES2 affects the pharmacokinetics (PK) and pharmacodynamics (PD) of substrate drugs.
UNASSIGNED: This review provides an up-to-date overview of CES expression and activity regulations and examines their impact on the PK and PD of CES substrate drugs. The literature search was conducted on PubMed from inception to January 2024.
UNASSIGNED: Current research revealed modest associations of CES genetic polymorphisms with drug exposure and response. Beyond genomic polymorphisms, transcriptional and posttranslational regulations can also significantly affect CES expression and activity and consequently alter PK and PD. Recent advances in plasma biomarkers of drug-metabolizing enzymes encourage the research of plasma protein and metabolite biomarkers for CES1 and CES2, which could lead to the establishment of precision pharmacotherapy regimens for drugs metabolized by CESs. Moreover, our understanding of tissue-specific expression and substrate selectivity of CES1 and CES2 has shed light on improving the design of CES1- and CES2-activated prodrugs.

OBJECTIVE: CEL-related maturity-onset diabetes of the young (CEL-MODY, MODY8) is a special type of monogenetic diabetes caused by mutations in the carboxyl-ester lipase (CEL) gene. This study aimed to summarize the genetic and clinical characteristics of CEL-MODY patients and to determine the prevalence of the disease among Chinese patients with early-onset type 2 diabetes (EOD).
METHODS: We systematically reviewed the literature associated with CEL-MODY in PubMed, Embase, Web of Science, China National Knowledge Infrastructure and Wanfang Data to analyze the features of patients with CEL-MODY. We screened and evaluated rare variants of the CEL gene in a cohort of 679 Chinese patients with EOD to estimate the prevalence of CEL-MODY in China.
RESULTS: In total, 21 individuals reported in previous studies were diagnosed with CEL-MODY based on the combination of diabetes and pancreatic exocrine dysfunction as well as frameshift mutations in exon 11 of the CEL gene. CEL-MODY patients were nonobese and presented with exocrine pancreatic affection (e.g., chronic pancreatitis, low fecal elastase levels, pancreas atrophy and lipomatosis) followed by insulin-dependent diabetes. No carriers of CEL missense mutations were reported with exocrine pancreatic dysfunction. Sequencing of CEL in Chinese EOD patients led to the identification of the variant p.Val736Cysfs*22 in two patients. However, these patients could not be diagnosed with CEL-MODY because there were no signs that the exocrine pancreas was afflicted.
CONCLUSIONS: CEL-MODY is a very rare disease caused by frameshift mutations affecting the proximal VNTR segments of the CEL gene. Signs of exocrine pancreatic dysfunction provide diagnostic clues for CEL-MODY, and genetic testing is vital for proper diagnosis. Further research in larger cohorts is needed to investigate the characteristics and prevalence of CEL-MODY in the Chinese population.

Although 5‑fluorouracil (5‑FU)‑based chemotherapy is the major treatment for colorectal cancer, it has disadvantages such as systemic toxicity, lack of effectiveness and selectivity, and development of resistance. Capecitabine, a prodrug form of 5‑FU, was designed to overcome these drawbacks, to fulfill the need for more convenient therapy, and to improve safety, tolerability and intratumor drug concentration levels through a tumor‑specific conversion to the active 5‑FU drug. The purpose of the present review is to provide a comprehensive comparison between 5‑FU therapy and capecitabine. In the current review, anticancer drug classification was discussed and the development of capecitabine from the original fluorinated analogue (5‑FU) to overcome its drawbacks was explained. Specifically, 5‑FU is compared with capecitabine therapy regarding various properties, including drug metabolism, cellular mechanism, effect on the apoptosis pathway and cell cycle phases, safety and tolerability. Moreover, three metabolizing enzymes required for the activation of capecitabine to 5‑FU were discussed. Capecitabine, as monotherapy or in combination with other chemotherapies, exhibited improved drug efficacy and survival. However, the changes that mediate the chemoresistance of capecitabine treatment were classified as intracellular, extracellular or cell surface factors, or cell‑phenotype state. Future studies should examine the efficacy of capecitabine combined with novel and safe drugs other than chemotherapeutic agents that play a role in the inhibition of tumor initiation, progression and metastasis.

Mammalian carboxylesterases (CESs) are essential members of serine esterase hydrolase superfamily, which are widely distributed in many tissues including liver, intestine, lung and kidney. CESs play an important role in the metabolism of various xenobiotics including ester drugs and environmental toxicants, and also participate in lipid homeostasis, so the development of CESs activity detection techniques are of great significance for drug discovery and biomedical research. With the rapid development of separated and detection technologies such as chromatography, capillary electrophoresis, fluorescent probe-based detection technology, bioluminescent sensor and colorimetric sensor in recent decade, the research of physiological functions of CESs have make huge breakthrough. This review summarizes the development and application of CESs activity detection techniques, as well as comparatively analyzes the characteristics of various detection techniques. The information and knowledge represented here will help the researchers carry out various biochemical studies for understanding activation mechanism and role of CESs in drug metabolism.

UDP-glucuronosyltransferase (UGT) and esterases are recognized as the most important non-P450 enzymes because of their high contribution to drug metabolism. UGTs catalyze the transfer of glucuronic acid to hydroxyl, carboxyl, or amine groups of compounds, whereas esterases hydrolyze compounds that contain ester, amide, and thioester bonds. These enzymes, in most cases, convert hydrophobic compounds to water-soluble metabolites to facilitate the elimination of compounds from the body. Information about these enzymes is steadily increasing, although our knowledge is still behind our understanding of P450. This review gives an overview of recent findings in UGT and esterases studies focusing on tissue distribution, gene regulation, substrate and inhibitor specificity, and species differences. In particular, the absolute protein content of UGT isoforms and esterases in human tissues could be available. In the field of esterases, it is becoming clear that enzymes other than carboxylesterase are involved in drug hydrolysis. In addition, there is an interesting interplay between UGTs and esterases in the formation and hydrolytic deglucuronidation of acyl-glucuronide, which is considered to be a reactive metabolite. With the growing awareness of the importance of non-P450 enzymes in drug development, issues that should be resolved are discussed.

High resolution karyotype was performed in 13 retinoblastoma patients. A mosaic pattern for del(13)(q14.1;q14.3) was found in a girl with sporadic bilateral retinoblastoma and midface dysmorphism. In addition, 162 cases of 13q aberrations were reviewed, including 140 retinoblastoma patients and 22 non-penetrance 13q14 deletions. Some epidemiological and genetic involvements are discussed.