Cytochrome metabohsm

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. 

Cytochrome P-450 is frequently the oxygenase which detoxifies xenobiotics, including herbicides. Blocking the metaboHsm of a herbicide increases the activity or delays the inactivation, thus increasing the effectiveness of such herbicides as chlortoluron [15545-48-9] and bentazon [25057-89-0]... 

Two and twelve moles of ATP are produced, respectively, per mole of glucose consumed in the glycolytic pathway and each turn of the Krebs (citrate) cycle. In fat metaboHsm, many high energy bonds are produced per mole of fatty ester oxidized. Eor example, 129 high energy phosphate bonds are produced per mole of palmitate. Oxidative phosphorylation has a remarkable 75% efficiency. Three moles of ATP are utilized per transfer of two electrons, compared to the theoretical four. The process occurs via a series of reactions involving flavoproteins, quinones such as coenzyme Q, and cytochromes. 

Fig. 4. The cycle of events involved in cytochrome (Cyt) P q (Cyt P450 Fe + ) mediated dmg metaboHsm where NADP is nicotinamide disphosphate and...

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

The principal route of macroHde excretion is by way of the Hver. Effects of macrohdes on hepatic metaboHc enzymes, particularly cytochrome P-450, have been studied in order to identify and reduce potential interference with metaboHsm of other dmgs (21—23,444—447). Several macrohdes are initially... 

Fungal cytochrome P450 involved in sterol metabohsm... 

Kyerematen GA, Morgan M, Warner G, Martin LF, VeseU ES (1990) Metabohsm of nicotine by hepatocytes, Biochem Pharmacol 40(8) 1747-1756 Le Gal A, Dreano Y, Lucas D, Berthou F (2003) Diversity of selective environmental substrates for human cytochrome P450 2A6 alkoxyethers, nicotine, coumarin, N-nitrosodiethylamine, and N-nitrosobenzylmethylamine, Toxicol Lett 144(1) 77-91 Lee BL, Benowitz NL, Jacob P 3rd (1987) Influence of tobacco abstinence on the disposition kinetics and effects of nicotine, Clin Pharmacol Ther41(4) 474 79 Lee BL, Jacob P 3rd, Jarvik ME, Benowitz NL (1989) Food and nicotine metabolism, Pharmacol Biochem Behav 33(3) 621-625... 

Ishizaki, T., and Horai, Y. (1999) Review article cytochrome P450 and the metabohsm of proton pump inhibitors—emphasis on rabeprazole. Aliment. Pharmacol. Ther. 13, 27-36. 

When the drug concentrations are below the K, Clj is essentially independent of drug concentration. The processes of drug metaboHsm are similar to other en2ymat-ic processes. For instance most oxidative processes (cytochrome P450) obey Michaelis-Menten kinehcs ... 

Kinetic parameters of metabolism of fluorinated analogues of propanolol by cytochrome enzyme (recombinant CYP1A2) have been determined. They clearly indicate that the A-dealkylation process was 10-fold lower for the N—CH2CF3 compound with respect to propanolol itself. Hydroxylation of the naphthalene ring process is not observed in the case of propanolol but it becomes the major process with the fluoro analogue (Figure 3.13)." The same decreased metabohsm trend has also been observed with lower pKa values for CYP2D6 cytochrome enzyme." ... 

Sai, Y, Yang, T.J., Krausz, K.W, Gonzalez, F.J. Gelboin, H.V. (1999) An inhibitory monoclonal antibody to human cytochrome P450 2A6 defines its role in the metabohsm of coumarin, 7-ethoxycoumarin and 4-nitroanisole in human liver. Pharmacogenetics, 9, 229-237... 

Watkins, P. B. Role of cytochromes P450 in drug metabohsm and hepatotoxicity. Semin. Liver Dis. 10, 235,1990. 

Within aerobic biology, the harvesting of the oxidative energy of O2 is fundamental to oxidative metabohsm. Because this is accomplished via the electron-transfer oxidation of four cytochrome c(Fe ) molecules ( pH , +0.3 V vs. NHE) per O2, the challenge is to facilitate the reduction of O2 via four one-electron steps, each with a potential greater than +0.4 V versus NHE at pH 7 (equation 125). The thermodynamics for the uncatalyzed electron-transfer reduction of O2 does not meet this criterion (equation 126) especially for the initial pH-independent electron transfer to O2. 

Protease inhibitors have been shown to reduce viral RNA concentration ( viral load ), increase the CD4 coimt and improve survival when used in combination with other agents and compared against placebo. They are extensively metabolised by isoenzymes of the cytochrome P450 system, notably by CYP 3A4 which is involved in the metabohsm of many drugs. Plasma t for each of these is in the range 2-i h. The drugs have broadly similar therapeutic effects and include ... 

Johansson, I. Lundqvist, E. Bertilsson, L. Dahl, M.L. Sjoqvist, F. Ingelman-Sundberg, M. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabohsm of debrisoquine. Proc. Natl Acad. Sci. 1993, 90, 11,825-11,829. 

Cytochromes P450 (P450) form a large family of heme enzymes that catalyze a diversity of transformations including epoxidation, hydroxylation and heteroatom oxidation. The enzymes are involved in the metabohsm of many... 

Both in vitro and in vivo metabohsm has to be studied. Most of the results reviewed are from in vitro studies. The metabolites are generated by the use of recombinant enzymes, e.g., related to the cytochrome P450 (CYP) complex, by the use of subcellular fractions, e.g., microsomes, cytosols, or S9 fractions, or by the use of hepatocytes or liver slices. In the case of in vivo metabolism studies, the metabohtes are generated in living animals or humans, and analysis is performed in urine, plasma, bile, and/or faeces. 

---