Cytochrome P450 enzymes oxidation

Likewise, in the final case, C, spin angular momentum on a metallic centre can be more or less closely situated with respect to an unpaired electron (or electrons) situated on a non-metallic centre. One example of this situation concerns the Compound I intermediate of oxidative cytochrome P450 enzymes. This compound involves two unpaired electrons on a formally Fe(IV)-0 iron oxo core, high-spin coupled to form a local S=1 spin contribution, with a third unpaired electron residing in the n orbitals of the porphyrin ligand [8]. Coupling between the two spin components can lead to both doublet and quartet states. 

The numerous biotransformations catalyzed by cytochrome P450 enzymes include aromatic and aliphatic hydroxylations, epoxidations of olefinic and aromatic structures, oxidations and oxidative dealkylations of heteroatoms and as well as some reductive reactions. Cytochromes P450 of higher animals may be classified into two broad categories depending on whether their substrates are primarily endogenous or xenobiotic substances. Thus, CYP enzymes of families 1-3 catalyze... 

In the second oxidation method, a metalloporphyrin was used to catalyze the carotenoid oxidation by molecular oxygen. Our focus was on the experimental modeling of the eccentric cleavage of carotenoids. We used ruthenium porphyrins as models of cytochrome P450 enzymes for the oxidation studies on lycopene and P-carotene. Ruthenium tetraphenylporphyrin catalyzed lycopene oxidation by molecular oxygen, producing (Z)-isomers, epoxides, apo-lycopenals, and apo-lycopenones. 

Shimada, T., Yamazaki, H., Mumura, M., Inui, Y., Guengerich, F. P., Interindividual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals studies with liver microsomes of 30 Japanese and Caucasians, J. Pharmacol. Exp. Then 1994, 270, 414-423. 

Yamazaki, H., Suzuki, M., Tane, K., Shimada, N., Nakajima, M. and Yokoi, T. (2000) in vitro inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human cytochrome P450 enzymes comparison with pioglitazone and rosiglitazone. Xenobiotica, 30 (1), 61—70. 

H. Cai, F. P. Guengerich, Acylation of Protein Lysines by Trichloroethylene Oxide , Chem. Res. Toxicol. 2000,13, 327 - 335 H. Cai, F. P. Guengerich, Reaction of Trichloroethylene and Trichloroethylene Oxide with Cytochrome P450 Enzymes Inactivation and Sites of Modification , Chem. Res. Toxicol. 2001, 14, 451 - 458. 

Another reaction of dehalogenation, the oxidative dehalogenation of haloalkyl groups, summarized in Fig. 11.3,b (Chapt. 8 in [50]), has also been observed in mammals and other organisms. Here, the haloalkane is oxidized by a cytochrome P450 enzyme to form a hydroxylated intermediate that loses HX to become a carbonyl derivative. The latter is then reduced by dehydrogenases to the corresponding alcohol (Fig. 11.3,c), or, when the carbonyl derivative is an aldehyde, oxidation to the acid can occur (Fig. 11.3,c). 

A less common reactive species is the Fe peroxo anion expected from two-electron reduction of O2 at a hemoprotein iron atom (Fig. 14, structure A). Protonation of this intermediate would yield the Fe —OOH precursor (Fig. 14, structure B) of the ferryl species. However, it is now clear that the Fe peroxo anion can directly react as a nucleophile with highly electrophilic substrates such as aldehydes. Addition of the peroxo anion to the aldehyde, followed by homolytic scission of the dioxygen bond, is now accepted as the mechanism for the carbon-carbon bond cleavage reactions catalyzed by several cytochrome P450 enzymes, including aromatase, lanosterol 14-demethylase, and sterol 17-lyase (133). A similar nucleophilic addition of the Fe peroxo anion to a carbon-nitrogen double bond has been invoked in the mechanism of the nitric oxide synthases (133). 

Antipyrine (l,2-dihydro-l,5-dimethyl-2-phenyl-3H-pyrazole-3-one) is anM-me-thylated analgesic drug which is primarily metabolized in the liver by microsomal cytochrome P450 enzymes [3, 61-68] (Fig. 3). The three main oxidative metabolites of antipyrine are 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine. 

The flavin monooxygenases (FMOs) are a family of five enzymes (FMO 1-5) that operate in a manner analogous to the cytochrome P450 enzymes in that they oxidize the drug compound in an effort to increase its elimination. Though they possess broad substrate specificity, in general they do not play a major role in the metabolism of drugs but appear to be more involved in the metabolism of environmental chemicals and toxins. 

Dihydroartemisinin (DHA) is the active metabolite of acetalic derivatives of artemisinin (artemether, artesunate). Oxidation by cytochrome P450 enzymes or/and hydrolysis provides DHA, which is itself poorly stable in vivo. Indeed, the corresponding oxonium ion, a precursor of inactive metabolites by ring opening or by glucuronidation, can easily be formed (Figure 4.15). 

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