Cytochrome P-450 systems

Riviere, J.-L. and Cabanne, F. (1987). Animal and plant cytochrome P-450 systems. Biochimie 69, 743-752. 

Nagy I, F Compernolle, K Ghys, J Vanderleyden, R De Mot (1995a) A single cytochrome P-450 system is involved in degradation of the herbicides EPTC (S-ethyl dipropylthiocarbamate) and atrazine by Rhodococcus sp. N186/21. Appl Environ Microbiol 61 2056-2060. 

Nagy 1, G Schools, F Compermolle, P Proost, J Vanderleyden, R De Mot (1995b) Degradation of the thiocar-bamate herbicide EPTC S-ethyl dipropylcarbamoylthioate and biosafening by Rhodococcus sp. strain N186/21 involve an inducible cytochrome P-450 system and aldehyde dehydrogenase. J Bacterial 177 676-687. 

Warburton EJ, AM Magor, MK Trower, M Griffin (1990) Characterization of cyclohexane hydroxylase involvement of a cytochrome P-450 system from a cyclohexane-grown Xanthobacter sp. EEMS Microbiol Lett 66 5-10. 

Phenols also constitute a major source of xenobiotic exposure to the body in the form of drugs and environmental pollutants. Oxidative metabolism of these compounds can lead to physiological damage, therefore the metabolism of these compounds is of great interest. LCEC has been a powerful tool for investigating the metabolism of aromatic compounds by the cytochrome P-450 system LCEC... 

B3b system, although it certainly is not ruled out for the M. capsulatus (Bath) enzyme. In comparison to the cytochrome P-450 system, the hydroxylation mechanism for both MMO systems either has a rebound rate constant which is much larger and/or it takes place by an alternative pathway to classical radical rebound. 

With the exception of pravastatin which is mainly metabolized by isomerization in the gut to a relatively inactive metabolite, the other statins undergo biotransformation by the cytochrome P-450 system. Therefore, drugs known to inhibit statin metabolism should be used cautiously. The time until maximum effect on lipids for statins is generally 4 to 6 weeks. 

Ethinyl estradiol is metabolized in the liver via the cytochrome P-450 system. It is metabolized primarily via CYP450 3A4. When reviewing drug interactions of oral contraceptives, it is important to keep in mind that antibiotic administration during contraceptive use may decrease the efficacy of many combined contraceptives. Refer to Table 45-4 for a list of common drug interactions seen with oral contraceptives.1,31... 

Effects on Vitamin D Metabolism. Lead interferes with the conversion of vitamin D to its hormonal form, 1,25-dihydroxyvitamin D. This conversion takes place via hydroxylation to 25-hydroxyvitamin D in the liver followed by 1-hydroxylation in the mitochondria of the renal tubule by a complex cytochrome P-450 system (Mahaffey et al. 1982 Rosen and Chesney 1983). Evidence for this effect comes primarily from studies of children with high lead exposure. 

Saito et al. (134) found that the cytosolic nitroreductase activity was due to DT-diaphorase, aldehyde oxidase, xanthine oxidase plus other unidentified nitroreductases. As anticipated, the microsomal reduction of 1-nitropyrene was inhibited by 0 and stimulated by FMN which was attributed to this cofactor acting as an electron shuttle between NADPH-cytochrome P-450 reductase and cytochrome P-450. Carbon monoxide and type II cytochrome P-450 inhibitors decreased the rate of nitroreduction which was consistent with the involvement of cytochrome P-450. Induction of cytochromes P-450 increased rates of 1-aminopyrene formation and nitroreduction was demonstrated in a reconstituted cytochrome P-450 system, with isozyme P-448-IId catalyzing the reduction most efficiently. 

F. Scheller, R. Renneberg, G. Strand, K. Pommerening, and P. Mohr, Electrochemical aspects of cytochrome P-450 system from liver microsomes. Bioelectrochem. Bioenerg. 4, 500-507 (1977). 

Iron complexes or microsomal nonheme iron are undoubtedly obligatory components in the microsomal oxidation of many organic compounds mediated by hydroxyl radicals. In 1980, Cohen and Cederbaum [27] suggested that rat liver microsomes oxidized ethanol, methional, 2-keto-4-thiomethylbutyric acid, and dimethylsulfoxide via hydrogen atom abstraction by hydroxyl radicals. Then, Ingelman-Sundberg and Ekstrom [28] assumed that the hydroxylation of aniline by reconstituted microsomal cytochrome P-450 system is mediated by hydroxyl radicals formed in the superoxide-driven Fenton reaction. Similar conclusion has been made for the explanation of inhibitory effects of pyrazole and 4-methylpyrazole on the microsomal oxidation of ethanol and DMSO [29],... 

Microsomal oxidation of amines and phenols may proceed by different ways. For example, it has been shown [42] that phentermine (2-methyl-l-phenyl-2-propylamine) is hydro-xylated to /V-hydroxyphcntcrminc by rat liver cytochrome P-450 system through a normal cytochrome P-450 way ... 

Salmon AG, Nash JA, Walkin CM, et al. 1985. Dechlorination of halocarbons by microsomes and vesicular reconstituted cytochrome P-450 systems under reductive conditions. Br J Ind Med 42 305-311. 

Servent and colleagues [52] reported that GTN is metabolised in rat liver microsomes by an NADPH-dependent cytochrome P-450 system, yielding GDN, glyceryl mononitrate (GMN) and NO. Moreover, Schroeder and Schroer [53] showed that inhibitors of cytochrome P-450 reduce cGMP stimulation by GTN in kidney epithelial cells. 

Cytochrome P-450 systems are also present in both smooth muscle [54, 5 5] and endothelial [56] cells. In studies of hepatic [57] and aortic [58] microsomes, Bennett and colleagues showed that bioconversion of GTN to GDN was NADPH dependent and was inhibited by the cytochrome P-450 inhibitor, SKF 525A. In hepatic microsomes, moreover, conversion of GTN led to activation of sGC [59]. 

Heptachlor, chlordane, and endosulfan (another cyclodiene pesticide) were shown to inhibit hepatocyte gap junctional intercellular communication (Ruch et al. 1990). All three pesticides showed similar dose-response relationships. Further testing with chlordane and heptachlor indicated that inhibition of the cytochrome P-450 system had no effect on this response. These results suggest that the interference with intercellular communication is not directly tied into the effects of these cyclodienes on the P-450 system. 

Hepatic metabolism and excretion in the bile play major roles in the elimination of both vinblastine and vincristine in humans (52) small amounts of vincristine and vinblastine, of the order of 10% of the administered dose, are excreted unchanged in urine. Renal clearance of vinblastine has been reported to be less than 10% of total serum clearance 53). Vinblastine has been reported to inhibit a polymorphic cytochrome P-450 system in human hepatic microsomes, but the concentrations required were much higher than those observed in clinical settings (54). 

Cytochrome P-450 system.The metabolism of saquinavir is mediated by cytochrome P-450, with the specific isoenzyme CYP3A4 responsible for 90% of the hepatic metabolism. Additionally, saquinavir is a substrate for P-Glycoprotein (Pgp). Therefore, drugs that affect CYP3A4 and/or Pgp may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other drugs that are substrates for CYP3A4 or Pgp. 

These results compare well with those from other methodologies (35-36-37-38-39), including some using porphyrin-derived catalysts, that had been conceived also on the analogy with the cytochrome P-450 system. 

Table VII shows the Increase In cytochrome P-450 content In mlcrosomes from southern armyworm larval midguts resulting from dietary exposure to several cyclic monoterpenes ( ). It also shows a closely corresponding Increase In the rate of NADPH oxidation when pyrethrum Is the substrate (R) being oxidised. The microsomal cytochrome P-450 system Is arranged as outlined In Figure 6, consisting of a terminal heme-lron protein that In the oxidised (Fe3+) state binds the substrate (R). The complex undergoes two reductions during which bound molecular oxygen Is converted to free radical species, one of which Is Inserted In the substrate molecule, and the other one forms water. The reductions...

Clomethiazole has an elimination half-life of about 4 hours after a single bolus. When administered by intravenous infusion half-lives approaching 20 hours have been reported. The drug is a very powerful inhibitor of the cytochrome P-450 system. It occasionally causes haemolysis. BUTYROPHENONES Haloperidol... 

Drugs metabolized via the cytochrome P-450 system (ie, cyclosporine, disulfiram)... 

Various sulfur-containing compounds, including thioamides, thioureas, thiols, thioethers and disulfides, are oxidized by this enzyme system. However, unlike cytochromes P-450, it cannot catalyze hydroxylation reactions at carbon atoms. It is clear that this enzyme system has an important role in the metabolism of xenobiotics, and examples will appear in the following pages. Just as with the cytochromes P-450 system, there appear to be a number of isoenzymes, which exist in different tissues, which have overlapping substrate specificities. 

Let us look at the major types of oxidation reaction catalyzed by the cytochromes P-450 system. 

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