Sequence comparisons indicated a huge similarity between cytochromes P450 identified in man and bacteria, and suggested that the superfamily cytochrome P450 first originated from a common ancestral gene some three billion years ago.
The superfamily cytochrome P450 was named in 1961, because of the 450-nm spectral peak pigment that cytochrome P450 has when reduced and bound to carbon monoxide. In the early 1960s, P450 was thought to be one enzyme, and by the mid 1960s it was associated with drug and steroid metabolism.
However, the membrane-associated and hydrophobic nature of the enzyme system impeded purification, and the number of proteins involved could not be accurately counted. Advances in mRNA purification in the early 1980s allowed to isolate the first cDNA encoding a complete cytochrome P450 (CYP) protein, and thereafter, results of many cloning studies have revealed a large number of different enzymes.
Advances in molecular biology and genomics facilitated the biochemical characterisation of individual P450 enzymes:
* The cytochromes P450 act on many endogenous substrates, introducing oxidative, peroxidative, and reductive changes into small molecules of widely different chemical structures. Substrates identified to date include saturated and unsaturated fatty acids, eicosanoids, sterols and steroids, bile acids, vitamin D3 derivatives, retinoids, and uroporphyrinogens.
* Many cytochrome P450 enzymes can metabolise various exogenous compounds including drugs, environmental chemicals and pollutants, and natural plant products.
* Metabolism of foreign chemicals frequently results in successful detoxication of the irritant; However, the actions of P450 enzymes can also generate toxic metabolites that contribute to increased risks of cancer, birth defects, and other toxic effects.
* The expression of many P450 enzymes is often induced by accumulation of a substrate.
* The ability of one P450 substrate to affect the concentrations of another in this manner is the basis for so-called drug-drug interactions, which complicate treatment.