Cytochrome Compound

Epoxidation consists of adding an oxygen atom between two C atoms in an unsaturated system, as shown in Reactions 7.3.2 and 7.3.3. It is a particularly important means of metabolic attack on aromatic rings that abound in many xenobiotic compounds. Cytochrome P-450 is involved in epoxidation reactions. Both of the epoxidation reactions shown below have the effect of increasing the toxicides of the parent compounds, a process called intoxication. Some epoxides are unstable,... 

Desulfovibrio vutgaris, adenylyl sulfate reductase of, 281, 282-284,285 Detergent, see also spedfie compounds cytochrome h reductase and, 154-156, 161, 163... 

It was not until 1925 that Keilin confirmed MacMunn s spectroscopic studies and named the new class of compounds cytochromes , which means cellular pigments. In an elegant series of experiments, he found that the four-banded spectrum rapidly appeared in the flight muscles of a live wax moth during muscular activity, and then disappeared when the moth rested. Keilin s experiments were the first to establish a direct correlation between the chemical state of a cellular component and the physiological state of the organism. Keilin identified the absorption bands at 604 nm, 566 nm, and 550 nm as the a-bands of three different cytochromes, a, b, and c, respectively. The broadband at 520 nm is due to overlapping /3-bands of the three cytochromes. A more detailed account of the discovery of cytochromes can be found in Keilin. ... 

Compounds having the 16,17 ketal, eg, budesonide, amcinonide, fluocinonide, halcinonide, triamcinolone acetonide, and flurandrenohde, also undergo metabohsm by routes that parahel that of cortisol metabohsm. Unsymmetrical acetals such as budesonide are also metabolized by routes not available to the more metabohcahy stable symmetrical 16a,17a-isopropyhdiene-dioxysubstituted compounds (desonide, flunisohde, and triamcinolone acetonide). Isozymes within the cytochrome P450 3A subfamily are thought to catalyze the metabohsm of budesonide, resulting in formation of 16a-hydroxyprednisolone and 6P-hydroxybudesonide (19,20) (Fig. 3) in addition to the more common metabohc steps (oxidation via reduction of A, etc). 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

Other compounds of this general class which have been found to have antiestrogenic properties include the cytochrome P-450 inhibitor, SKF 525A P02-33-0](Sl) (24) JV, JV-diethyl-2-[(4-phenylmethyl)phenoxy]ethanamine [98774-23-3] (DPPE)(58) (42) /-Butylphenoxyethyl diethylamine [57586-10-4] (BPEA)(59) (43) and cyclofenil [110042-18-7] (60, R = C H ) (24) analogues. 

Organosulfur Compounds. These compounds, Hsted in Table 8, are used in a variety of appHcations, including cooling water, paint, and metalworking. Methylenebisthiocyanate hydroly2es rapidly at a pH above 8 to cyanate ion which complexes with ferric iron to poison the cytochrome systems (36). 

N—Fe(IV)Por complexes. Oxo iron(IV) porphyrin cation radical complexes, [O—Fe(IV)Por ], are important intermediates in oxygen atom transfer reactions. Compound I of the enzymes catalase and peroxidase have this formulation, as does the active intermediate in the catalytic cycle of cytochrome P Q. Similar intermediates are invoked in the extensively investigated hydroxylations and epoxidations of hydrocarbon substrates cataly2ed by iron porphyrins in the presence of such oxidizing agents as iodosylbenzene, NaOCl, peroxides, and air. 

The abihty of iron to exist in two stable oxidation states, ie, the ferrous, Fe ", and ferric, Fe ", states in aqueous solutions, is important to the role of iron as a biocatalyst (79) (see Iron compounds). Although the cytochromes of the electron-transport chain contain porphyrins like hemoglobin and myoglobin, the iron ions therein are involved in oxidation—reduction reactions (78). Catalase is a tetramer containing four atoms of iron peroxidase is a monomer having one atom of iron. The iron in these enzymes also undergoes oxidation and reduction (80). 

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

MDR-ABC Transporters. Figure 3 Detoxification cellular mechanisms. X, toxic compound X-OH, oxidized toxic compound GS-X, conjugated toxic compound OATP, organic anion transporting proteins CYPs, cytochromes GSH, glutathion UDPGIcUA, Uridine 5-diphosphoglucuronic acid PAPs, 3-phosphoadenylylsulfate. 

Proton Pump Inhibitors and Acid Pump Antagonists retinoid X receptor (RXR) and is also activated by various lipophilic compounds produced by the body such as bile acids and steroids. PXR heterodimerized with RXR stimulates the transcription of cytochrome P450 3A monooxygenases (CYP3A) and other genes involved in the detoxification and elimination of the... 

Cytochrome P-450 — an effective catalyst of the oxidation of organic compounds by peroxides. D. I. Metelitsa, Russ. Chem. Rev. (Engl. Transl), 1981, 50,1058-1073 (147). 

Catalysis. Cytochrome P-450 model compounds catalyze the epoxidation of alkenes by hypochlorite ions.16 A typical catalyst is OMn(TMP)L+. 

Aerobic respiration. Many organisms carry out aerobic respiration in which enzymes remove electrons from organic compounds and pass them through a chain of carriers including flavoproteins and cytochromes located in intracellular membranes (Fig. 3-4) until finally they are used to reduce oxygen to produce water. ATP is produced by an enzyme called ATPase, that is located in the cell membrane, and the process is driven by a proton gradient across the membrane. 

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