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Published on: October 19, 2013
Age-specific pulmonary cytochrome P-450 3A1 expression in postnatal and adult rats
Kimberly C Day1, Charles G Plopper, Michelle V Fanucchi
1Dept. of Veterinary Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, Univ. of California, One Shields Ave., Davis, CA 95616, USA.
Insights
Neonatal rats have detectable levels of cytochrome P-450 3A1 (CYP3A1) in their lungs. While CYP3A1 mRNA levels are similar in young and adult rats, protein levels and enzyme activity are lower in neonates, impacting respiratory health.
Area of Science:
- Pulmonary toxicology
- Developmental biology
- Biochemistry
Background:
- Respiratory diseases are a leading cause of mortality in young children, particularly in polluted urban areas.
- Neonatal animals are more vulnerable to lung injury from certain chemicals than adults, despite lower expression of key detoxifying enzymes like cytochrome P-450s (CYP450s).
- The role of CYP450 3A (CYP3A), a significant enzyme in drug and toxicant metabolism, during lung development is not well understood.
Purpose of the Study:
- To investigate the age-specific expression and activity of CYP3A1 in the developing lungs of Sprague-Dawley rats.
- To compare CYP3A1 mRNA and protein levels, as well as enzymatic activity, between neonatal (7-day-old) and adult rats.
Main Methods:
- Quantitative analysis of CYP3A1 messenger RNA (mRNA) expression in airway cells.
- Immunohistochemical detection of CYP3A1 protein localization in ciliated and nonciliated cells.
- Measurement of CYP3A1 enzyme activity in lung tissue.
Main Results:
- CYP3A1 mRNA expression levels were comparable between 7-day-old and adult rats.
- CYP3A1 protein expression was 28% lower, and enzymatic activity was 23% lower in neonatal rat airways compared to adults.
- Unlike other CYP450s, CYP3A1 protein was found in both ciliated and nonciliated cells, with a diffuse distribution in neonates and apical localization in adults.
Conclusions:
- Postnatal rat lungs possess detectable CYP3A1.
- CYP3A1 mRNA expression is not age-dependent, but protein levels and enzyme activity exhibit a clear age-dependent pattern.
- These findings suggest that developmental changes in CYP3A1 protein and activity may influence the susceptibility of young animals to pulmonary toxicants.
Abstract:
A major cause of death and illness in children under the age of five, most living in polluted cities, is respiratory disease. Previous studies have shown that neonatal animals are more susceptible to bioactivated pulmonary cytotoxicants than adults, despite lower expression of the pulmonary cytochrome P-450s (CYP450s) thought to be involved in bioactivation. One CYP450 that is well documented in the bioactivation of many drugs and environmental toxicants in adult lung, but whose expression has not been evaluated during postnatal pulmonary development, is CYP450 3A (CYP3A). We compared age-specific expression of CYP3A1 in 7-day-old and adult male Sprague-Dawley rats. Unlike those shown for previously studied pulmonary CYP450s, expression levels for CYP3A1 mRNA in differentiating airway cells of postnatal rats are the same as in fully differentiated airway cells of adults. CYP3A1 protein expression (28%) and enzymatic activity (23%) were lower in postnatal airways compared with adults. Although other CYP450 immunoreactive proteins are primarily expressed in nonciliated cells, immunoreactive CYP3A1 protein was expressed in both ciliated and nonciliated cells in postnatal and adult rat proximal airways. CYP3A1 protein is detected diffusely throughout ciliated and nonciliated cells in 7-day-old rats, whereas it is only detected in the apex of these cells in adult rats. This study demonstrates that the lungs of postnatal rats have detectable levels of CYP3A1 and that CYP3A1 mRNA expression appears not to be age dependent, whereas steady-state CYP3A1 protein levels and enzyme activity show an age-dependent pattern.
