The first experimental evidence relating to cytochromes P450 was discovered in
1955 by Axelrod [78] and Brodie et al.
[79], who identified an enzyme system in the endoplasmic
reticulum of the liver which was able to oxidize xenobiotic
compounds. In 1958 Garfinkel [80] and Klingenberg
[81] detected a CO binding pigment in liver
microsomes which had an absorption maximum at 450nm (See Figure
). This was demonstrated to be a hemoprotein of the
b-type class in 1964 [82, 83] which was named
cytochrome P450 after the strong feature in its absorption
spectrum. Electron spin resonance spectroscopy suggested that P450 is
a low spin ferric hemoprotein [84] with a thiol residue
as an axial haem ligand [85, 86, 87]. This lead to
explanations for the unusual Soret peak position and its perturbation
upon the binding of substrates and other chemicals in terms of charge
transfer modulated by the Fe - S bond
[88, 89, 90]. Raman spectroscopy provided
confirmation of the presence of an Fe - S bond and identified this as
a covalently bonded cysteine residue [91]. In 1985 a full
structure of 
(CYP101), a bacterial P450 from
Pseudomonas putida, was obtained
[92, 93]. Subsequently, crystal structures have been
obtained for the 
[94] and 
enzymes [95] as well as for in complex with substrate [96], carbon
monoxide [97], inhibitors [98, 99] and
substrate analogues [100, 101, 102].
Figure: The
absorption spectrum of cytochrome P450-CO complex showing the
characteristic Soret peak at approximately 450nm (Created using data
from [103] for 
).
The first metabolic pathway shown to involve P450 was that for C21-hydroxylation of steroids in the adrenal corticoid system [103, 104]. Its rôle as the terminal oxidase was confirmed for the liver microsomal system in the endoplasmic reticulum [105].
Originally discovered in mammalian liver microsomal preparations, P450s have subsequently been discovered in every class of biotica. In addition, although found mainly in the liver [106], P450s have been identified in many other organs [107]. P450s are responsible for the metabolism of numerous endogenous compounds [107, 108] as well as an enormous range of xenobiotic compounds [109] including many toxins and carcinogens [110] as well as drugs.