P-450 monooxygenase

DMN oxidative demethylation has been shown to be a liver mi-crosome cytochrome P-450 monooxygenase (10) Lotlikar et al. (11) found that a reconstituted enzyme system, consisting of cytochrome P-450, NADPH-cytochrome P-450 reductase and phosphatidyl choline was effective in catalyzing the demethylation of DMN. The most commonly accepted mechanism for the oxidative demethylation of DMN and, by extension, of other dialkyInltrosamlnes is shown in Scheme 1. 

Narhi LO, AJ Fulco (1986) Characterization of a catalytically self-sufficient 119,000-Dalton cytochrome P-450 monooxygenase induced by barbiturates in Bacillus megaterium. J Biol Chem 261 7160-7169. 

Metabolism of BP mediated by the cytochrome P-450 monooxygenase system forms three classes of products phenols, dihydrodiols and quinones. Formation of phenols and dihydrodiols is obtained by an initial electrophilic attack of an enzyme-generated oxygen atom. 

Adults given a single oral dose of either PCB 47 at 87.6 mg/kg body weight (BW), PCB 77 at 87.6 mg/kg BW, or Aroclor 1242 at 100-500 mg/kg BW. Quail were killed 48 h postdosing and liver and intestine analyzed for porphyrins and cytochrome P-450 monooxygenases Adults fed diets for 30 days containing 100 mg cadmium/kg diet, 100 mg Aroclor 1260/kg diet, or mixture of 100 mg cadmium plus 100 mg Aroclor 1260/kg Fed in diet for 25 days at 5, 50, or 500 mg Aroclor 1260/kg diet... 

While the cytochrome P-450 monooxygenase reaction described in Eq. (1) often involves hydroxylation of carbon, many other reactions are catalyzed by these enzyme systems. These reactions include oxidation of nitrogen and sulfur, epoxidation, dehalogenation, oxidative deamination and desulfuration, oxidative N-, O-, and S-dealkylation, and peroxidative reactions (56). Under anaerobic conditions, the enzyme system will also catalyze reduction of azo, nitro, N-oxide, and epoxide functional groups, and these reductive reactions have been recently reviewed (56, 57). Furthermore, the NADPH-cytochrome P-450 reductase is capable of catalyzing reduction of quinones, quinonimines, nitro-aromatics, azoaromatics, bipyridyliums, and tetrazoliums (58). 

Cocaine-mediated hepatotoxicity has been associated with the conversion of cocaine to norcocaine and further oxidation products. The enzymes involved in in vitro hepatic oxidative N-demethylation of cocaine (192) were investigated (237), and two different enzymatic pathways appear to be important in the formation of the hepatotoxic metabolite. Cytochrome P-450 monooxygenases accomplish the direct N-demethylation of cocaine to norcocaine (194) as confirmed by induction and inhibition studies (Scheme 42). The second pathway for cocaine N-demethylation involves formation of cocaine /V-oxide (193) as an intermediate and two enzymes. A flavin-containing monooxygenase is first thought to convert cocaine to cocaine /V-oxide, followed by cytochrome P-450-... 

A particular toxicity associated with the administration of interferon to humans and experimental animals has been depression of the cytochrome P-450 monooxygenase (MFO) metabolizing enzymes. As a consequence of MFO inhibition following treatment with IFN, the sleep-time of mice treated with hexabarbital is increased, as is the toxicity of acetaminophen (Stebbing and Week, 1984). Possible effects on the metabolism of chemotherapeutic agents or other drugs processed by the P-450 MFOs should be anticipated. 

Disulfoton causes neurological effects in humans and animals. The mechanism of action on the nervous system depends on the metabolism of disulfoton to active metabolites. The liver is the major site of metabolic oxidation of disulfoton to disulfoton sulfoxide, disulfoton sulfone, demeton S-sulfoxide and demeton S-sulfone, which inhibit acetylcholinesterase in nervous tissue. These four active metabolites are more potent inhibitors of acetylcholinesterase than disulfoton. Cytochrome P-450 monooxygenase and flavin adenine dinucleotide monooxygenase are involved in this metabolic activation. The active metabolites ultimately undergo nonenzymatic and/or enzymatic hydrolysis to more polar metabolites that are not toxic and are excreted in the urine. 

Livingstone, D. R. Moore, M.N. Lowe, D.M. Casci, C. Farrar, S. 1985, Responses of the cytochrome P-450 monooxygenase system to diesel oil in the common mussel Mytilus edulis L. and the periwinkle, Littorina littorea L. Aquat. Toxicol. 1 79-91. 

He teaches courses in bioorganic and bioinorganic chemistry (in particular on the role of metals in biology and on the iron-heme enzymes such as peroxidases and cytochromes P-450 monooxygenases). 

Transition metal hydroperoxo species are well established as important intermediates in the oxidation of hydrocarbons (8,70,71). As they relate to the active oxygenating reagent in cytochrome P-450 monooxygenase, (porphyrin)M-OOR complexes have come under recent scmtiny because of their importance in the process of (poiphyrin)M=0 formation via 0-0 cleavage processes (72-74). In copper biochemistry, a hydroperoxo copper species has been hypothesized as an important intermediate in the catalytic reaction of the copper monooxygenase, dopamine P-hydroxylase (75,76). A Cu-OOH moiety has also been proposed to be involved in the disproportionation of superoxide mediated by the copper-zinc superoxide dismutase (77-78). Thus, model Cun-OOR complexes may be of... 

This enzyme, a P-450 monooxygenase, catalyzes the NADPH-dependent conversion of flavanones to fla-vones. 

Chemical Mechanisms of the Cytochrome P-450 Monooxygenase-Catalyzed Metabolism of Phosphorothionate Triesters... 

Contents Low-molecular-weight organosulfur compounds in nature / Eric Block—Chemical mechanisms of the cytochrome P-450 monooxygenase-catalyzed metabolism of phosphorothionate triesters / R. A. Neal —Sulfur in propesticide action / T. R. Fukuto and M. A. H. Fahmy—[etc.]... 

Latunde-Dada, A.O. et al., Elavonoid 6-hydroxylase from soybean (Glycine max L.), a novel plant P-450 monooxygenase. J. Biol. Chem., 276, 1688, 2001. 

Cytochromes P-450 MFO system. The majority of these reactions are catalyzed by one-enzyme system, the cytochromes P-450 monooxygenase system, which is located particularly... 

The cytochromes P-450 monooxygenase system is actually a collection of isoenzymes, all of which possess an iron protoporphyrin IX as the prosthetic group. The monomer of the enzyme has a molecular weight of 45,000 to 55,000. The enzyme is membrane bound within the endoplasmic reticulum. Cytochromes P-450 are closely associated with another vital component of the system, NADPH cytochrome P-450 reductase. This is a flavoprotein, which has 1 mol of FAD and 1 mol of FMN per mol of apoprotein. The monomeric molecular weight of the enzyme is 78,000. The enzyme transfers two electrons to cytochromes P-450, but one at a time. There only seems to be one reductase, which serves a group of isoenzymes of cytochromes P-450, and consequently, its concentration is 1/10 to 1/30 that of cytochromes P-450. 

Figure 4.2 The catalytic cycle of the cytochrome(s) P-450 monooxygenase (MFO) system. aFor explanation of step 4, see text. Abbreviation Cyp, cytochromes P-450 MFO, mixed function oxidase. Source From Ref. 1.

Schenkman, J.B. and Kupfer, D., Eds., Hepatic Cytochrome P-450 Monooxygenase System, Pergamon Press, Oxford, 1982. 

Fev=0 and Mnv=0 have also recently emerged as plausible reactive intermediates in the oxidation of hydrocarbons by iodosylbenzene, amine N-oxide, percarboxylic acids, hypochlorites, etc. catalyzed by iron or manganese porphyrins. Current opinion favors Fev=0 species as the active oxidant in cytochrome P-450 monooxygenases.54 55... 

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