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Evolution of the cytochrome P450 genes
D W Nebert1, D R Nelson, R Feyereisen
1Laboratory of Developmental Pharmacology, National Institute of Child Health and Human Development, Bethesda, MD 20892.
Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|October 1, 1989
Summary
The P450 gene superfamily, crucial for drug metabolism, shows ancient origins and rapid evolution, potentially driven by ecological interactions. Understanding P450 gene regulation is vital for accurate toxicity assessments across species.
Area of Science:
- Biochemistry
- Genetics
- Evolutionary Biology
Background:
- The cytochrome P450 (P450) gene superfamily comprises over 78 members in 14 families.
- This superfamily exhibits ancient divergent evolution, with an estimated ancestral gene age exceeding 2 billion years.
- Recent rapid expansion of P450 genes, particularly in family II, has occurred over the last 800 million years.
Purpose of the Study:
- To explore the evolutionary history and diversification of the P450 gene superfamily.
- To investigate the potential drivers of P450 gene expansion, such as inter-species interactions.
- To examine the implications of P450 gene diversity for interspecies extrapolation of toxicity and cancer data.
Main Methods:
- Comparative genomics and phylogenetic analysis to trace P450 gene evolution.
- Analysis of P450 gene family expansion patterns in relation to ecological pressures.
- Review of P450 gene regulation mechanisms and electron donor interactions across different phyla.
Main Results:
- The P450 superfamily has a deep evolutionary root and has experienced significant expansion, notably in family II, possibly due to 'animal-plant warfare'.
- Species-specific P450 gene presence/absence highlights challenges in extrapolating toxicity and cancer data between rodents and humans.
- Enzyme induction typically reflects increased gene transcription, though exceptions exist, and understanding P450 regulation mechanisms can be advanced by comparing responses across phyla.
Conclusions:
- The evolutionary trajectory of P450 genes is complex, influenced by ancient divergence and recent adaptive radiations.
- Caution is warranted when extrapolating toxicological findings across species due to P450 gene repertoire differences.
- Investigating P450 electron donor interactions and regulation across diverse taxa offers insights into eukaryotic evolution and P450 functional diversity.