A major class of oxidative transformations was initially characterized in 1955 by O.Hayaishi in Japan1 and H.S.Mason in the United States2. This class of Oxygenases had requirements for both an oxidant (molecular Oxygen) and a reductant (Reduced NADP) and hence was given the trivial name "mixed-function oxidases."
(Pictured below: P-420 Chart Graph)
An understanding of the biochemical nature of these reactions grew out of early studies on liver pigments by Garfinkel3 and Klingenberg4 who observed in liver microsomes an unusual carbon monoxide binding pigment with an absorbance maximum at 450 nm. This pigment was ultimately characterized as a cytochrome by Omura and Sato5. Through the use of detergent solubilization of microsomes and interaction with isocyanide ligands, they showed that the resultant "P-420" was indeed a cytochrome with typical a, b, and Soret absorption bands.
(Pictured left: Tsuneo Omura; pictured above: Ryo Sato)
Spectrophotometric studies of adrenal microsomes by Cooper and co-workers6 determined that the adrenal cortex also contained a CO-binding pigment similar to that reported by Klingenberg to be present in the liver. The function of this unique cytochrome (called P450) was initially revealed in 1963 in studies by Estabrook, Cooper, and Rosenthal7using microsomes from the adrenal cortex for the catalysis of the hydroxylation of 17-hydroxyprogesterone to deoxycorticosterone. Relying on earlier studies by Ryan and Engel8 that had shown that the adrenal C-21 hydroxylation reaction was inhibited by CO and the inhibition could be reversed by white light, Estabrook, Cooper and Rosenthal performed classic photoactivation experiments and proved that this cytochrome was the oxygen combining component in the C-21 hydroxylation of steroids.
In the 35 years since the identification of cytochrome P450 as the terminal component of oxygenation reactions the field has grown from an area of narrow interest to drug metabolism scientists to a major field of interest to molecular biologists, pharmacologists, biochemists and physicians. From the isolation of membrane-bound P450 by Lu and Coon9 in 1969 to the first crystallization of a mammalian P450 in 1999 by Eric Johnson and co-workers10 the area of P450 research has established the important role of P450s in controlling the disposition of drugs and other xenobiotics.
Ref:1O.Hayaishi, Proc.Plen.Session, 6th Int.Cong.Biochem.New York, July 1964, p.31.2 Mason, H.S., Adv.Enzymology 19:74 (1957) 3D. Garfinkel, Arch.Biochem.Biophys.77:493-509 (1958)4 M. Klingenberg, Arch.Biochem.Biophys.75:376 (1958) 5T. Omura, and R. Sato,J.Biol.Chem.239:2370 (1964)6 D.Y.Cooper, S.Levin, S.Narasimhulu, O.Rosenthal and R.W.Estabrook, Science 147:400 (1965) 7R.W.Estabrook, D.Y.Cooper, and O. Rosenthal, Biochem.Zeit. 338:741 (1963)8K.Ryan and L. Engel,J.Biol.Chem. 225:103 (1957)9Lu, A.Y.H., Junk, K.W., and Coon, M.J., J.Biol. Chem.244:3714-3721(1969)10Williams, P.A., Cosme, J., Sridhar, V. and Johnson, E.F.,J.Inorg.Biochem. 31:183-190(2000)
10/2/2016 » 10/6/2016
The 21st International Symposium on Microsomes and Drug Oxidations
10/27/2016 » 10/28/2016
ISSX Workshop: Translating Preclinical Data to Human Clearance and Pharmacokinetics