Cytochrome P-450 mediated metabolism

Wienkers, L.C., Allievi, C., Hauer, M.J. and Wynalda, M.A. (1999) Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metabolism and Disposition, 27 (11), 1334-1340. 

Figure 4. Proposed scheme for Cytochrome P-450 mediated metabolism (inactivation and activation) of procarcinogens (e.g. PAHs).

Desaturation of alkyl groups. This novel reaction, which converts a saturated alkyl compound into a substituted alkene and is catalyzed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA) (2-n-propyl-4-pentanoic acid) (Fig. 4.29). The mechanism proposed involves formation of a carbon-centered free radical, which may form either a hydroxy la ted product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450-mediated metabolism yields 4-ene-VPA (2-n-propyl-4pentenoic acid), which is oxidized by the mitochondrial p-oxidation enzymes to 2,4-diene-VPA (2-n-propyl-2, 4-pentadienoic acid). This metabolite or its Co A ester irreversibly inhibits enzymes of the p-oxidation system, destroys cytochrome P-450, and may be involved in the hepatotoxicity of the drug. Further metabolism may occur to give 3-keto-4-ene-VPA (2-n-propyl-3-oxo-4-pentenoic acid), which inhibits the enzyme 3-ketoacyl-CoA thiolase, the terminal enzyme of the fatty acid oxidation system. 

Walseth F, Toftgard R, Nilsen OG. 1982. Phthalate esters. I Effects on cytochrome P-450 mediated metabolism in rat liver and lung, serum enzymatic activities and serum protein levels. Arch Toxicol 50 1-10. 

The effects of carbon disulfide on the microsomal drug metabolizing system were demonstrated in rats by Freundt et al. (1975). Exposure of rats by inhalation to low concentrations of carbon disulfide (20-400 ppm for 8 hours) inhibited microsomal drug metabolism. This was reflected by increased hexobarbital sleep times. Pretreatment of rats with SKF-525A, an inhibitor of cytochrome P-450-mediated metabolism, reduced the liver damage from carbon disulfide in phenobarbital-pretreated animals (Bond and DeMatteis 1969). 

Various EETs have been measured in tissues as well as physiological fluids such as urine (G. FitzGerald, 1990). Biologically active lipids, originally defined as an endothelium-derived hyperpolarizing factor and an inhibitor of Na /K ATPase found in the thick ascending loop of Henley cells, were structurally characterized as 1 (/ ), 2(5)-EET and 20-HETE, both derived from cytochrome P-450-mediated metabolism of AA [35]. Interestingly, the EETs can readily form CoA esters and participate in reacylation of... 

In kidney, diltiazem and the atrial natriuretic peptide act together with Mn(II) in controlling haemodynamics [621,622]. In liver, ethanol alters the levels of a number of trace metals, including Mn(II) [623], while Mn(II) itself reduces the effects of aflatoxin and enhances the cytochrome P-450 mediated metabolism of hexabarbitol-type drugs [624,625]. In the nervous system, the effects of ischaemia are modulated by Ca-channel blockers such as Mn(II) [626]. Mn(II) ions have also been reported to modulate or inhibit the transient outward current in cultured sensory neurons or in taste nerve responses [627,628]. In pancreas beta-cells, interactions between the fluxes of Mn(II) and Ca(II) have also been observed [629]. 

Harder PA, DP O Keefe, JA Romesser, KJ Leto, CA Omer (1991) Isolation and characterization of Strepto-myces griseolus deletion mutants affected in cytochrome P-450-mediated herbicide metabolism. Mol Gen Genet 227 238-244. 

Figure 1. Simplified scheme for the electron transfer in the Cytochrome P-450 mediated monooxygenase activity. In the liver, the fiavoprotein is Cystochrome c reductase. R is the compound being metabolized. NAD and Cytochrome bs have...

Drug interactions No drug interaction studies have been conducted with Avonex. Other interferons have been found to reduce cytochrome P-450-mediated drug metabolism. Hepatic microsomes isolated from Avonex-treated rhesus monkeys showed no influence on hepatic P-450 enzyme metabolism activity. 

In addition to their well established role in catalyzing the metabolism of a wide variety of naturally occurring and synthetic xenobiotics, cytochrome P-450-mediated mixed-function oxidases are of critical Importance in the biosynthesis and regulation of the major hormones (ecdysteroids and juvenile hormone) that control insect growth and development. The characteristics of the mixed-function oxidases involved in the synthesis of insect hormones are described and the possibility that the enzymes might represent potential targets for insect control is discussed. 

The epoxidase catalyzing the 10,11-epoxidation of methyl farnesoate in homogenates of corpora allata from Locusta miqratoria has been studied in detail and has been shown to be a cytochrome P-450-mediated monooxygenase associated with the microsomal fraction. The enzyme is strictly dependent on NADPH and requires oxygen (36). It is sensitive to inhibition by carbon monoxide (36) and to offier compounds such as methyl enedioxyphenyl compounds and imidazoles that are well established inhibitors of the cytochrome P-450-mediated monooxygenases involved in xenobiotic metabolism (37-39). 

Interest in fungal metabolism as a model for that of higher organisms has been noted briefly in Chapter 4, Section 4.3.6, and reactions catalyzed by cytochrome P-450 mediated in both prokaryotes and eukaryotes have been discussed in Chapter 4, Section 4.4.I.2. The use of microorganisms, particularly fungi, to produce hydroxylated sterols of therapeutic interest has been extensively explored, and greatest attention has been directed to fungal hydroxylation of... 

K Zhang, F Lepage, G Cuvier, J Astoin, MS Rashed, TA Baillie. The metabolic fate of stiripentol in the rat. Studies on cytochrome P-450-mediated methylenedioxy ring cleavage and side chain isomerism. Drug Metab Dispos 18 794, 1990. 

Fig. 6. Three irnportam oxidative pathways for the metabolism of polyunsaturated fatty acids. A. The principal steps in the formation of prostaglandin endoperoxides from arachidonic acid. B. Likely mechanism for the formation of hydroperoxy cis.trans conjugated fatly acids by autooxidalion or by lipoxygena.sc.s. In the latter case, positional as well as stereospecificity arc normally found. The formed hydroperoxides may then be enzymatically transformed into leukotrienes (not shown) or to hydroxy acids. C. The enzymatic sequence in cytochrome P-450 mediated oxygenation. The first electron is donated from NADPH via the f lavoprotein (Fp) NADPH-cytochrome-P-450-reductase. while the second electron comes either from NADPH or NADH. In this way the monooxygenase enzymes inlrrxluce one oxygen from air into the substrate.

SKF-525A, metyrapone, ellipticine, clotrimazole), indicating that the reaction is cytochrome P-450-mediated (Den Besten and Livingstone 1989). Steroid metabolism has been extensively studied in echinoderms and cytochrome P-450-mediated reactions are indicated, e.g. hydroxylation of progesterone to 17a-hy-droxyprogesterone in pyloric caeca (600 g supernatant) of A. rubens (Voogt et al. 

Two more factors contributing to the persistence of xenobiotics in polychaetes, molluscs, crustaceans and echinoderms, and presumably other marine invertebrates, are the formation of macromolecular adducts and the slow release of free metabolites. The incorporation of PAH into more stable compartments , possibly as a result of cytochrome P-450-mediated adduct formation, is particularly evident in molluscs (see Fig. 3). The metabolites of many xenobiotics are lost more slowly than the parent compound, resulting in a build-up in the tissues during both exposure and subsequent depuration periods. The primary function of metabolism, therefore, appears to be detoxication, by preventing the formation of specific reactive metabolites and, probably more importantly, the non-specific toxic action of lipophilic xenobiotics caused by their penetration of membrane systems. Loss of metabolites down a concentration gradient occurs, reducing body burden of the xenobiotic, but is obviously limited by the absence or ineffectiveness of specific transport and excretory systems for the polar metabolites. 

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