P enzyme

Because LCEC had its initial impact in neurochemical analysis, it is not, surprising that many of the early enzyme-linked electrochemical methods are of neurologically important enzymes. Many of the enzymes involved in catecholamine metabolism have been determined by electrochemical means. Phenylalanine hydroxylase activity has been determined by el trochemicaUy monitoring the conversion of tetrahydro-biopterin to dihydrobiopterin Another monooxygenase, tyrosine hydroxylase, has been determined by detecting the DOPA produced by the enzymatic reaction Formation of DOPA has also been monitored electrochemically to determine the activity of L-aromatic amino acid decarboxylase Other enzymes involved in catecholamine metabolism which have been determined electrochemically include dopamine-p-hydroxylase phenylethanolamine-N-methyltransferase and catechol-O-methyltransferase . Electrochemical detection of DOPA has also been used to determine the activity of y-glutamyltranspeptidase The cytochrome P-450 enzyme system has been studied by observing the conversion of benzene to phenol and subsequently to hydroquinone and catechol... 

St. John s wort Increase metabolism of COCs via induction of various cytochrome P-450 enzymes Decrease efficacy of COCs avoid use with COCs... 

The majority of antiretroviral medications are metabolized by the cytochrome P-450 enzyme system (CYP). Therefore, it is important to review patient medication profiles for drugs that may interact with antiretroviral drugs. 

Shimada, T. et al. (1994). Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals studies with liver micro-somes of 30 Japanese and 30 Caucasians. /. Pharmacol. Exp. Ther., 270,414-23. 

The PDMS-membrane-occluded FePcY was the first room temperature catalytic membrane and the first solid catalyst dispersed in dense organic polymer.169 The catalytic system mimics the cytochrome P-450 enzyme and can oxidize alkanes at room temperature with rates comparable to those of the... 

Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery, J. Controlled Release 1999, 62, 25-31. 

Sterols Adrenal cortex, testes, ovaries Synthesis and degradation Haem Fe, P-450 enzymes... 

Cytochrome P-450. Cytochrome P-450 enzymes consist of a large number of haem-containing mono-oxygenases which catalyze aliphatic and aromatic hydroxylations, epoxidations, as well as other oxidation reactions thus, these enzymes are able to cleave aromatic C-H bonds and also... 

STADLER, R., ZENK, M.H., The purification and characterization of a unique cytochrome P-450 enzyme from Berberis stolonifera plant cell cultures, J. Biol. Chem., 1993,268, 823-831. 

Recent work in our laboratories has confirmed the existence of a similar pathway in the oxidation of vindoline in mammals (777). The availability of compounds such as 59 as analytical standards, along with published mass spectral and NMR spectral properties of this compound, served to facilitate identification of metabolites formed in mammalian liver microsome incubations. Two compounds are produced during incubations with mouse liver microsome preparations 17-deacetylvindoline, and the dihydrovindoline ether dimer 59. Both compounds were isolated and completely characterized by spectral comparison to authentic standards. This work emphasizes the prospective value of microbial and enzymatic transformation studies in predicting pathways of metabolism in mammalian systems. This work would also suggest the involvement of cytochrome P-450 enzyme system(s) in the oxidation process. Whether the first steps involve direct introduction of molecular oxygen at position 3 of vindoline or an initial abstraction of electrons, as in Scheme 15, remains unknown. The establishment of a metabolic pathway in mammals, identical to those found in Strep-tomycetes, with copper oxidases and peroxidases again confirms the prospective value of the microbial models of mammalian metabolism concept. 

The measurement of the ethoxyresorufin-O-deethylase (EROD) activity is another sensitive parameter to detect the effects of paper mill industrial effluents on living organisms in the receiving waters. The EROD activity is a measure of the activity of the cytochrome P-450 enzyme system, which plays a central role in the transformation and elimination of xenobiotics. Increased EROD activity has been shown as far as 40 km from pulp mills, and EROD induction in fish caused by pulp mill effluents remains after biological treatment [60]. It is specified that EROD activity and erythrocytic nuclear abnormalities are induced by abietic and dehydroabietic acid [60]. 

No information is available as to whether metabolism of -hexane in children differs from that of adults. No studies were located comparing metabolism in young and adult animals. The toxicity of -hexane results from biotransformations yielding the active metabolite, 2,5-hexanedione. The initial step is an oxidation to 2-hexanol catalyzed by a cytochrome P-450 enzyme. Some P-450 enzymes are develop-mentally regulated (Leeder and Keams 1997). As the above discussion indicates, it is not completely clear which P-450 enzymes are involved in -hexane metabolism. 

If the neurotoxicity of /7-hexane was potentiated in this study by co-exposure to acetone, the level of n-hexane alone required to produce these effects would be higher than 58 ppm and the MRL level would be higher. Results from simulations with a PBPK model that accurately predicted /7-hexane blood and 2,5-hexanedione urine levels (Perbellini et al. 1986, 1990a) indicate that at concentrations of 50 ppm, the rate-limiting factor in /7-hexane metabolism is delivery to the liver, not metabolic activity. This suggests that at this concentration (and at the MRL concentration of 0.6 ppm), induction of P-450 enzymes in the liver by acetone or other chemicals would not affect the rate at which 2,5-hexanedione was produced. 

There is no experimental evidence adequate to evaluate whether metabolism of M-hcxanc is different in children. Similarly, there is no information available from animal experiments. The initial step in -hexane metabolism in animals is a hydroxylation step catalyzed by a P-450 enzyme. Since some of these enzymes are developmentally regulated, it would be of interest to know (1) if there are specific P-450 isozymes involved in -hexane hydroxylation and, (2) if so, are these isozymes known to be developmentally regulated ... 

Newcomb M, Letadic MH, Putt DA, et al. An incredibly fast apparent oxygen rebound rate-constant for hydrocarbon hydroxylation by cytochrome-P-450 enzymes. J Am Chem Soc 1995 117(11) 3312—3313. 

Ortiz de Montellano PR, Reich NO. Inhibition of cytochrome P-450 enzymes. In Ortiz de Montellano PR, ed. Cytochrome P-450, lsted. New York Plenum 1986. 

Characterization of human microsomal cytochrome P-450 enzymes. Annual Review of Pharmacology and Toxicology, 29, 241-264. 

Shimada, T., Yamazaki, H., Mimura, M., Inui, Y. and Guengerich, F.P. (1994) Interindividual variations inhuman liver cytochrome P-450 enzymes involved in... 

P-450 enzymes have been cloned and in vitro studies can be performed using these enzyme systems. Metabolic pathways can be studied by incubating the drug with the P-450 enzymes. Similarly, drug-drug interactions can be studied. 

In vitro assays are increasingly being used. Some of the reasons are cost, availability of more rapid results, and avoidance of negative publicity. Assays such as cytochrome P-450 enzymes, the Ames test, and the mouse lymphoma tk test are in vitro methods. For absorption studies, Caco-2 (Exhibit 5.9) and Madin-Darby canine kidney cell assays are now routinely used. Hepatocyte cell lines with metabolism capacity are being developed to test drug metabolism and toxicity. All these examples show that, where possible, pharmaceutical firms are gradually dispensing with animal studies. 

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