P-450 cytochrome oxidase

It has been found that cimetidine inhibits the P-450 cytochrome oxidase system in the liver. This is an important enzyme system in the metabolism of drugs and care must be taken if other drugs are being taken at the same time as cimetidine, since... 

Attention must be given to possible drug interactions when using cimetidine due to inhibition of drug metabolism (Section 13.11.). The other three H2 antagonists mentioned do not inhibit the P-450 cytochrome oxidase system and are less prone to such interactions. 

Bisbenzylisoquinoline alkaloids are dimeric benzyltetrahydroisoquinoline alkaloids that are known for their pharmacological activities. A well-described example is the muscle relaxant (+)-tubocurarine, which in crude form serves as an arrow poison for South American Indian tribes. In the biosynthesis of this broad class of dimeric alkaloids, it has been postulated that the mechanism of phenol coupling proceeds by generation of phenolate radicals followed by radical pairing to form either an inter- or intramolecular C - O or C - C bond. Enzyme studies on the formation of bisbenzylisoquinoline alkaloids indicated that a cytochrome P-450-dependent oxidase catalyzes C - O bound formation in the biosynthesis of berbamunine in Berberis cell suspension culture.15 This enzyme, berbamunine synthase (CYP80A1), is one of the few cytochromes P-450 that can be purified to... 

Fig. 10.3 Reaction catalyzed by the cytochrome P-450-dependent oxidase berbamunine synthase (CYP80A1). This enzyme creates a branchpoint in the (5)-reticuline biosynthetic pathway to form the bisbenzylisoquinoline alkaloids.

The 1-methylindole derivative (14) (see Table 7.1), which was marginally more potent than (13) in vitro, showed good oral activity in the BJ test in the rat (ED50 0.11 mg/kg). However, it potentiated the pentobarbitone sleeping time in the mouse, suggesting it had the capacity to bind to and inhibit the hepatic cytochrome P-450-linked oxidase enzyme system. Optical... 

Ferenczy, G. G. and Morris, G. M. (1989) The active site of cytochrome P-450 nifedipine oxidase a model-building study. J. Mol. Graph. 7, 206-11. 

The formation of superoxide has, moreover, been reported for cytochrome P-450, diamine oxidase, flavoproteins, and peroxidases... 

Bork RW, Muto T, Beaune PH, et al. Characterization of mRNA species related to human liver cytochrome P-450 nifedipine oxidase and the regulation of catalytic activity. J Biol Chem 1989 264 910-919. 

While the hydroxylases of the adrenals and other steroid producing tissues show some (variable) catalytic activity towards xenobiotics (e.g., benzo[a]pyrene) (17) this is probably fortuitous in nature and it seems that, in general, the enzymes are quite specific for their respective steroid substrates. Furthermore, the steroid hydroxylases of the endocrine system are not susceptible to the inductive effects of xenobiotics as are the cytochrome P-450-mediated oxidases of the liver and other tissues (17,18) indeed, this is not unexpected, since if they responded to the external environment in this way their critical homeostatic role would rapidly be compromized. 

Carbonic Anhydrase Cytochromes Cytochrome P-450 Aldehyde Oxidase Catalase, Peroxidase Hydrogenase Methylmalonyl Isomerase Kinase... 

R.S. Lloyd, and F.P. Guengerich (1986). Isolation and sequence determination of a cDNA clone related to human cytochrome P-450 nifedipine oxidase. Proc. Natl. Acad. Sci. USA 83, 8064-8068. 

The drug is observed to minimise the hepatic metabolism of such drugs that are eventually biotransformed by the cytochrome P-450 mixed oxidase system by way of either delaying the elimination or enhancing the serum levels of these pharmacologic agents. 

Early work on members of the cytochrome family established that the pattern of distribution varied more widely among bacteria than among eukaryotes. The extreme position is occupied by the anaerobic genus Clostridium, members of which have no cytochromes whatsoever (Keilin, 1933). The parasitic worms Ascaris lumbricoides var. suum (a nematode) and Moniezia expansa (a cestode) lack cytochrome P-450. This suggests that helminthicidal drugs can be designed which will persist in these parasites but be destroyed by the P-450-linked oxidases of their hosts (Douch, 1976). 

Araki K, Toma HE (2009) Supramolecular porphyrin model compounds for cytochrome p-450, cytochrome-c oxidase and photosynthetic systems. In Merce ALR, Felcman J, Recio MAE (eds) Molecular and supramolecular bioinorganic chemistry applications in medical sciences. Nova Science Publishers, New York, pp 83-136... 

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). 

Many examples of microbial hydroxylation of sterols/steroids have been reported. These hydroxylations usually involve mixed function oxidases which utilise molecular oxygen and cytochrome P-450. The reaction can be represented by ... 

CYP, cytochrome P-450 isoenzyme MAO, monoamine oxidase. Data from references 59-65. 

BUN, blood urea nitrogen CBC, complete blood cell count CNS, central nervous system CYP, cytochrome P-450 isoenzyme LFT, liver function test MAO, monoamine oxidase QTc, Q-T interval corrected for heart rate SCr, serum creatinine TMP-SMX, trimethoprim-sulfamethoxazole. 

Isoenzymes Structurally related enzyme proteins that catalyse very similar or identical reactions (e.g., monoamine oxidase A and B, cytochrome P-450). 

Figure 5. Metabolic activation pathways of BA. MFO abbreviates for the cytochrome P-450-containing mixed-function oxidases. The absolute configurations of the metabolites are as shown.

Oxidation is intimately linked to the activation of polycyclic aromatic hydrocarbons (PAH) to carcinogens (1-3). Oxidation of PAH in animals and man is enzyme-catalyzed and is a response to the introduction of foreign compounds into the cellular environment. The most intensively studied enzyme of PAH oxidation is cytochrome P-450, which is a mixed-function oxidase that receives its electrons from NADPH via a one or two component electron transport chain (10. Some forms of this enzyme play a major role in systemic metabolism of PAH (4 ). However, there are numerous examples of carcinogens that require metabolic activation, including PAH, that induce cancer in tissues with low mixed-function oxidase activity ( 5). In order to comprehensively evaluate the metabolic activation of PAH, one must consider all cellular pathways for their oxidative activation. 

A potentially powerful probe for sorting out the contribution of hydroperoxide-dependent and mixed-function oxidase-dependent polycyclic hydrocarbon oxidation is stereochemistry. Figure 9 summarizes the stereochemical differences in epoxidation of ( )-BP-7,8-dihydrodiol by hydroperoxide-dependent and mixed-function oxidase-dependent pathways (31,55,56). The (-)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (+)-anti-diol epoxide by both pathways whereas the (+)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (-)-anti-diol epoxide by hydroperoxide-dependent oxidation and to the (+)-syn-diol epoxide by mixed-function oxidases. The stereochemical course of oxidation by cytochrome P-450 isoenzymes was first elucidated for the methycholanthrene-inducible form but we have detected the same stereochemical profile using rat liver microsomes from control, phenobarbital-, or methyl-cholanthrene-induced animals (32). The only difference between the microsomal preparations is the rate of oxidation. 

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