Cytochrome P450 enzymes reactions

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... 

Rendic, S. DiCarlo, F. J. (1997). Human cytochrome P450 enzymes a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab. Rev., 29, 413-580. 

The membrane-attached cytochrome P450 enzymes are involved in a significant fraction of events associated with drug metabolism. Most of the cytochrome P450 (CYP) catalyzed reactions lead to the detoxification of xenobiotics, by forming hydrophilic metabolites that can be readily excreted from the body. 

The precursor, 7-dehydrocholesterol is converted by a non-enzymatic reaction to cholecalciferol (calciol). This reaction occurs in skin exposed to sunlight due to irradiation by UV-B light at a wavelength of about 300 nm. Cholecalciferol is transported via carrier proteins to the liver where hydroxylation at carbon-25 occurs in a reaction catalysed by a microsomal cytochrome P450 hydroxylase to form calcidiol. This compound travels to the kidney attached to specific binding proteins, where another cytochrome P450 enzyme, mitochondrial 1-a-hydroxylase, introduces a second hydroxyl group in to the molecule to form the active calcitriol. 

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). 

Shou M, Lin Y, Lu P, Tang C, Mei Q, et al. 2001. Enzyme kinetics of cytochrome P450-mediated reactions. Curr Drug Metab 2 17. 

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). 

In the liver s hepatocytes, the proportion represented by the sER is particularly high. It contains enzymes that catalyze so-called biotransformations. These are reactions in which apolar foreign substances, as well as endogenous substances—e. g., steroid hormones—are chemically altered in order to inactivate them and/or prepare them for conjugation with polar substances (phase I reactions see p. 316). Numerous cytochrome P450 enzymes are involved in these conversions (see p. 318) and can therefore be regarded as the major molecules of the sER. 

Kalgutkar, A.S., Obach, R.S. and Maurer, T.S. (2007) Mechanism-based inactivation of cytochrome P450 enzymes chemical mechanisms, structure-activily relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions. Current Drug Metabolism, 8, 407—447. 

Some selective serotonin re-uptake inhibitors are powerful inhibitors of cytochrome P450 enzymes and the metabolism of e.g. tricyclic antidepressants can be inhibited resulting in serious toxicity. Additive sedation can be expected when given in combination with CNS depressants such as benzodiazepines but also with alcohol. Selective serotonin re-uptake inhibitors should not be used in combination with monoamine oxidase inhibitors as fatal reactions have been reported. 

F. Ogliaro, N. Harris, S. Cohen, M. Filatov, S. R de Visser, and S. Shaik, A Model Rebound Mechanism of Hydroxylation by Cytochrome P450. Stepwise and Effectively Concerted Pathways, and Their Reactivity Patterns, J. Am. Chem. Soc. 2000,122, 8977. Calculations explain puzzling aspects of cytochrome P450 hydroxylation reactions in terms of two, different, reactive spin states of the enzyme. 

Suggestions about the metabolic pathway leading to " CO2 were provided by the work of Marker and Kulkami (1985, 1986). They showed that the microsomal metabolism of 2-nitropropane in mice resulted in the release of nitrite in a cytochrome P450-dependent reaction. In contrast to earlier results in rats, cnzx matic denitrification in mice did not require enzyme induction. 

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