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Tissue distribution and gender-divergent expression of 78 cytochrome P450 mRNAs in mice
Helen J Renaud1, Julia Yue Cui, Mohammed Khan
1Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Abstract:
Cytochrome P450 (Cyp) enzymes from the first four families (Cyp1-4) play a major role in metabolizing xenobiotics, affecting drug pharmacokinetics and chemical-induced toxicity. Due to cloning of the mouse genome, many novel Cyp isoforms have been identified, but their tissue distribution of expression is unknown. This study compared the tissue distribution of all 78 Cyps from the Cyp1-4 families in C57BL/6 mice providing not only an indication of which tissues novel Cyps may have their greatest importance but also a cohesive comparison of the tissue distribution of all Cyp1-4 isoforms. Transcripts of the 78 Cyps were quantified by multiplex suspension arrays and quantitative real-time PCR in 14 tissues. Hierarchical clustering indicated that in male mice, 52% of the Cyp species were expressed highest in liver, 10% in kidney, 10% in duodenum/jejunum, 10% in testes, 5% in lung, and < 4% in colon, brain, heart, and stomach. Female mice had a similar pattern of Cyp messenger RNA expression; however, compared with males, females had 7% more Cyps that were liver predominant, 2% more Cyps that were stomach predominant, but 1% less Cyps that were kidney and lung predominant. Differences in gender expression were observed in 29 of the Cyps, with 24 being higher in females than males. Additionally, the data suggest a correlation between the spatial arrangement of genes within a gene cluster and their organ-predominant expression, indicating a common regulatory mechanism may be present within these clusters. In conclusion, this study provides novel data on the tissue distribution and gender-divergent expression of 78 functional mouse Cyp isoforms.
Insights
This study maps the tissue expression of 78 mouse Cytochrome P450 (Cyp) enzymes. It reveals key organ distribution and gender-specific differences for these important drug-metabolizing enzymes.
Area of Science:
- Pharmacology and Toxicology
- Genomics and Bioinformatics
- Biochemistry
Background:
- Cytochrome P450 (Cyp) enzymes (Cyp1-4) are crucial for xenobiotic metabolism, influencing drug pharmacokinetics and toxicity.
- The identification of numerous novel Cyp isoforms in mice necessitates understanding their tissue expression patterns.
Purpose of the Study:
- To comprehensively map the tissue distribution of all 78 Cytochrome P450 (Cyp) isoforms from families 1-4 in C57BL/6 mice.
- To compare the tissue distribution across all Cyp1-4 isoforms and identify potential tissue-specific importance of novel Cyps.
- To investigate gender-specific differences in Cyp expression.
Main Methods:
- Quantification of transcripts for 78 Cyp isoforms across 14 tissues using multiplex suspension arrays and quantitative real-time PCR.
- Application of hierarchical clustering to analyze Cyp expression patterns in male and female mice.
- Correlation analysis between gene cluster organization and organ-predominant expression.
Main Results:
- Liver was the predominant site of expression for 52% of Cyp species in male mice, followed by kidney, duodenum/jejunum, and testes (10% each).
- Female mice exhibited a similar expression pattern but with a higher proportion of liver-predominant Cyps (+7%) and stomach-predominant Cyps (+2%), and slightly less kidney and lung predominant Cyps.
- Gender-divergent expression was observed in 29 Cyps, with 24 showing higher expression in females than males. A correlation between gene cluster arrangement and expression patterns suggests common regulatory mechanisms.
Conclusions:
- This study provides novel, comprehensive data on the tissue distribution of 78 mouse Cyp isoforms (Cyp1-4).
- Significant gender-specific differences in Cyp expression were identified, highlighting potential sex-based variations in xenobiotic metabolism.
- The findings suggest a link between gene organization within clusters and their tissue-specific expression, implying shared regulatory control.
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