Determination of cytochrome <i>P</i>-448 activity in biological tissues

Phillipson, Caroline E.; Godden, Patricia M. M.; Lum, Peck Y.; Ioannides, Costas; Parke, Dennis V.

doi:10.1042/bj2210081

Cited by 94 publications

(11 citation statements)

References 57 publications

(58 reference statements)

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“…Indeed, feprazone administration to rats had no effect on the 0-deethylation of ethoxyresorufin, a reaction catalyzed exclusively by the P450 I isoenzymes (23,24) and this was further confirmed by immunoblots which showed no increase in the levels of P450 I apoproteins. Since the P450 I family is involved in the activation of many chemical carcinogens, and is also induced by these (25), the present findings indicate that feprazone is unlikely to display genotoxicity through this mechanism.…”

Section: Discussionsupporting

confidence: 56%

Feprazone: An inducer of the P450 II B family of proteins in the rat

Smith

Ayrton

Chown

et al. 1990

J. Biochem. Toxicol.

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The ability of feprazone to induce the hepatic microsomal mixed-function oxidases was investigated in the rat, with emphasis being placed on the nature of the cytochrome P-450 family induced. Treatment with feprazone enhanced the p-hydroxylation of aniline and the dealkylations of benzphetamine and pentoxyresorufin but had no effect on the O-deethylation of ethoxyresorufin. The same treatment had no major effect on total cytochrome P-450 levels but increased the spectral interaction of metyrapone with reduced cytochrome P-450. Immunoblots employing monospecific polyclonal antibodies revealed that feprazone induces the apoprotein levels of the P450 II B, but not of the P450 I, family. It is concluded that feprazone is an inducer of the rat hepatic mixed-function oxidase system showing selectivity toward the P450 II B family.

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Section: Discussionsupporting

confidence: 56%

Feprazone: An inducer of the P450 II B family of proteins in the rat

Smith

Ayrton

Chown

et al. 1990

J. Biochem. Toxicol.

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“…A computer-graphic analysis of the molecular dimensions of IQ showed that it clearly meets the necessary criteria for interaction with the receptor and induction of cytochrome P450 I proteins. Pretreatment of rats with IQ gave rise to a dose-dependent increase in the 0-deethylation of ethoxyresorufin, the extent of increase being similar to that observed with aromatic amines [22, 431. This reaction is exclusively catalysed by the P450 I family of haemoproteins [44,45]. An increase was also seen in the 0-deethylation of 7-ethoxycoumarin, a reaction catalysed primarily by P450 I proteins [45].…”

Section: Discussionmentioning

confidence: 84%

Preferential induction of the rat hepatic P450 I proteins by the food carcinogen 2‐amino‐3‐methyl‐imidazo[4,5‐f]quinoline

Rodrigues

Ayrton

Williams

et al. 1989

European Journal of Biochemistry

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1. Administration of the food carcinogen, 2-amino-3-methyl-imidazo[4,5-flquinoline (IQ) to rats gave rise to significant dose-dependent increases in the microsomal 0-deethylations of ethoxycoumarin and ethoxyresorufin but had no effect on the 0-dealkylation of pentoxyresorufin and the NADPH-dependent reduction of cytochrome c, and decreased the N-demethylation of dimethylnitrosamine. Microsomal cytochrome b5 and total cytochrome P-450 levels decreased following the administration of the carcinogen.2. Hepatic microsomal preparations from IQ-treated animals were much more efficient than control in activating the premutagen 2-amino-6-methyldipyrido[l,2-u: 3',2'-dlimidazole to mutagenic intermediates in the Ames test.3. Immunoquantification of two of the major families of cytochrome P-450, namely P450 I and P450 I1 B, using ELISA techniques showed that treatment with IQ induced the apoprotein levels of the P450 I family but4. Immunoblot analysis employing polyclonal antibodies against P450 I revealed that IQ induced both isoenzymes of this family, namely P450 I A1 and A2.5. It is concluded that IQ is an inducer of the rat hepatic monooxygenases, selectively inducing the P450 I family as predicted by a computer-graphic analysis of its dimensions which showed that it is a large, essentially planar, molecule.The carcinogenicity of most chemicals is mediated, not by the parent form, but by reactive metabolic intermediates that readily interact with DNA initiating the process of tumourigenesis. By far the most prominent enzymes in the metabolic activation of chemical carcinogens are the ubiquitous monooxygenases whose terminal oxidase, cytochrome P-450, exists as a superfamily of proteins each of which confers to the system its characteristic substrate specificity [l].One of these families, namely P450 I (cytochromes P-448) appears to direct the metdbOhn of chemical carcinogens towards pathways that yield reactive species rather than inactive metabolites [2, 31. This family of isoenzymes is also involved in the activation of the aminoimidazo-azaarenes [4,5], which have been isolated from broiled fish and meat [6, 71. They are mutagens in a number of in vitro systems [8-111, activate a variety of oncogenes [12] and are potent animal carcinogens [I 3 -151. The prototype is IQ (2-amino-3-methylimidazo[4,5-flquinoline) whose activation proceeds through an initial N-hydroxylation to yield 2-amino-3-methyl-Nhydroxyimidazo[4,5-j~quinoline 1161, the proximate carcinogen, which undergoes further metabolism to generate the ultimate carcinogen [5]. The P450 I concentration in untreated animals is very small, immunologically calculated to be less than 5% of the total cytochrome P-450 content [17, 181, so that the activation of IQ is likely to be a minor pathway. However, many chemical carcinogens, such as the polycyclic The present study was therefore undertaken to establish if (a) IQ induces the rat hepatic monooxygenases, and (b) selectively induces the P450 I family that facilitates its activation. Since chemicals that inte...

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“…A form of cytochrome P-450 with high ERDE activity has been suggested as a form especially sensitive to induction by polycyclic aromatic hydrocarbons and cigarette smoking [Burke et al, 1978;Phillipson et al, 1984], also in human liver [Pelkonen et al, 1986]. …”

Section: Introductionmentioning

confidence: 99%

Characterization of Human Fetal Hepatic Cytochrome P-450-Associated 7-Ethoxyresorufin O-Deethylase and Aryl Hydrocarbon Hydroxylase Activities by Monoclonal Antibodies

Pasanen¹,

Pelkonen²,

Kauppila³

et al. 1987

Dev Pharmacol Ther

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Two cytochrome P-450-dependent enzyme activities, 7-ethoxyresorufin O-deethylase (ERDE) and aryl hydrocarbon hydroxylase (AHH) were measured in liver microsomes from 7 human fetuses. Monoclonal antibodies (MAb) to a 3-methylcholanthrene- induced (MAb 1-7-1) and a phenobarbital-induced (MAb 2-66-3) rat hepatic cytochrome P-450 were used to measure the contribution of the MAb-defined, epitope-specific cytochromes P-450 to the total reaction measured for the above activities. MAb 1-7-1 inhibited fetal hepatic ERDE activity to a variable extent (from 0 to 100%, 34 in average), but had only negligible effects on AHH activity (mean inhibition 9 %). The contribution of induction by cigarette smoking to the variability of ERDE inhibition by MAb 1-7-1 remained unclear. MAb 2-66-3 inhibited ERDE activity by 18% and AHH activity by 12%. In comparisons with earlier studies on adult liver and placental microsomes, the present results with fetal liver suggest that there are differences in cytochrome P-450- associated ERDE and AHH activities between these tissues, which might be due to different tissue-specific isoenzyme patterns.

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Determination of cytochrome P-448 activity in biological tissues

Cited by 94 publications

References 57 publications

Feprazone: An inducer of the P450 II B family of proteins in the rat

Feprazone: An inducer of the P450 II B family of proteins in the rat

Preferential induction of the rat hepatic P450 I proteins by the food carcinogen 2‐amino‐3‐methyl‐imidazo[4,5‐f]quinoline

Characterization of Human Fetal Hepatic Cytochrome P-450-Associated 7-Ethoxyresorufin O-Deethylase and Aryl Hydrocarbon Hydroxylase Activities by Monoclonal Antibodies

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