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History and Background

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 gif). 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 tex2html_wrap_inline3174 (CYP101), a bacterial P450 from Pseudomonas putida, was obtained [92, 93]. Subsequently, crystal structures have been obtained for the tex2html_wrap_inline3176 [94] and tex2html_wrap_inline3178 enzymes [95] as well as for tex2html_wrap_inline3174 in complex with substrate [96], carbon monoxide [97], inhibitors [98, 99] and substrate analogues [100, 101, 102].

   figure1346
Figure: The absorption spectrum of cytochrome P450-CO complex showing the characteristic Soret peak at approximately 450nm (Created using data from [103] for tex2html_wrap_inline3182 ).

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.


next up previous contents
Next: The P450 Catalytic Cycle Up: Cytochromes P450 Previous: Cytochromes P450

Matthew Segall
Wed Sep 24 12:24:18 BST 1997