Ontogenic expression of human carboxylesterase-2 and cytochrome P450 3A4 in liver and duodenum: Postnatal surge and organ-dependent regulation

Abstract

Human carboxylesterase-2 (CES2) and cytochrome P450 3A4 (CYP3A4) are two major drug metabolizing enzymes that play critical roles in hydrolytic and oxidative biotransformation, respectively. They share substrates but may have opposite effect on therapeutic potential such as the metabolism of the anticancer prodrug irinotecan. Both CES2 and CYP3A4 are expressed in the liver and the gastrointestinal tract. This study was conducted to determine whether CES2 and CYP3A4 are expressed under developmental regulation and whether the regulation occurs differentially between the liver and duodenum. A large number of tissues (112) were collected with majority of them from donors at 1-198 days of age. In addition, multi-sampling (liver, duodenum and jejunum) was performed in some donors. The expression was determined at mRNA and protein levels. In the liver, CES2 and CYP3A4 mRNA exhibited a postnatal surge (1 versus 2 months of age) by 2.7 and 29 fold, respectively. CYP3A4 but not CES2 mRNA in certain pediatric groups reached or even exceeded the adult level. The duodenal samples, on the other hand, showed a gene-specific expression pattern at mRNA level. CES2 mRNA increased with age but the opposite was true with CYP3A4 mRNA. The levels of CES2 and CYP3A4 protein, on the other hand, increased with age in both liver and duodenum. The multi-sampling study demonstrated significant correlation of CES2 expression between the duodenum and jejunum. However, neither duodenal nor jejunal expression correlated with hepatic expression of CES2. These findings establish that developmental regulation occurs in a gene and organ-dependent manner.

Age-Dependent Absolute Abundance of Hepatic Carboxylesterases (CES1 and CES2) by LC-MS/MS Proteomics: Application to PBPK Modeling of Oseltamivir In Vivo Pharmacokinetics in Infants

“…In a limited number of liver tissue samples from children between 0 and 10 years of age, the observed CES1 protein expression was 4-fold lower than that in adult samples (Yang et al, 2009). Consistent with our data, Shi et al (2011) and Chen et al (2015) have also reported age-dependent relative changes in CES1 and CES2 hepatic activity. The suggested variability in age-dependent CES1 protein expression level is confirmed in this study and compared with the adult data.…”

Age-Dependent Human Hepatic Carboxylesterase 1 (CES1) and Carboxylesterase 2 (CES2) Postnatal Ontogeny

“…Consistent with this expectation, Shi et al (2011) reported an approximate 2-fold increase in mean relative CES1 protein levels in hepatic S9 fractions from donor samples between 5 weeks and 6.5 months of age and adults (.18 years of age). Similar results have recently been reported for CES2 (Chen et al, 2015).…”

Developmental Changes in Pharmacokinetics and Pharmacodynamics

“…The same holds true for CYP3A4 mRNA expression where a significantly higher mRNA expression has been found in young adults but also a much higher expression in the first year of life as compared to 1‐ to 6‐ and 6‐ to 17‐year‐olds. Recent data show the level of liver CYP3A4 mRNA to be positively correlated with age, whereas duodenal CYP3A4 mRNA showed a more complex and almost opposite pattern …”

“…It was shown that intestinal GST participates in the first‐pass extraction of this drug, showing an upregulated activity in children younger than 5 years of age . Chen and colleagues measured CES2 mRNA and protein in duodenal samples from human donors of various ages and showed an increase with advancing age, reaching adult values at 0.5‐1 year of age. However, despite this developmental pattern of intestinal CES2, the prodrugs candesartan cilexetil and olmesartan medoxomil showed the same PK profile after oral dosing in children as in adults …”