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Biomedical subjects

D V Parke

Publications and source records attributed to D V Parke.

At least 73 records · Page 4Linked to original sources
PubMed1989

Adverse reactions of imidazole antifungal agents: computer graphic studies of cytochrome P-450 interactions.

The imidazole antifungal agents give rise to adverse reactions and clinically relevant drug interactions. This is due to lack of specificity of the antifungal agents that interact avidly not only with the fungal but also with mammalian cytochrome P-450 proteins. A computer graphic technique capable of predicting the interaction of these structurally-related imidazoles with fungal and mammalian cytochrome P-450 proteins is described. This prediction is achieved by comparing the molecular conformation of these drugs with lanosterol, the substrate of the fungal cytochrome P-450, and with phenobarbitone, an inducing agent of a family of mammalian cytochrome P-450, toward which the antifungal agents show highest inhibitory activity.

Animals↗
PubMed1989

Molecular orbital studies of oxygen activation and mechanisms of cytochromes P-450-mediated oxidative metabolism of xenobiotics.

Molecular dimensions and molecular orbital calculations of the electronic structures of 56 substrates, inhibitors and inducers of the cytochromes P-448 and other families of the cytochromes P-450 are reported. Substrates of the cytochromes P-448 are shown to be planar molecules with relatively large values of area/depth2, and to have electronic structures with relatively low values for delta E, the difference in energy between the frontier orbitals (E(LEMO)- E(HOMO)). Substrates of other families of the cytochromes P-450 are globular molecules, with relatively low values of area/depth2 and relatively high values of delta E. Molecular orbital calculations of the active oxygen species, singlet oxygen and superoxy anion, have also been made. Singlet oxygen is a poor electron donor (low values of E(HOMO)) but a good electron acceptor (low values of E(LEMO)), whereas superoxy anion is a good electron donor and a poor electron acceptor. Cytochrome P-448 substrates, which are good electron donors, would preferentially accept singlet oxygen, a good electron acceptor; substrates of the other families of cytochrome P-450, which are less effective electron donors, would preferentially accept superoxy anion, a good electron donor, although substrates of both cytochromes P-448 and other P-450s may accept both species of active oxygen. Together with recent published evidence, these data provide a greater understanding of the mode of activation of oxygen by the various families of the cytochromes P-450, and to the insertion of active oxygen into the substrates. Mechanisms are proposed for the oxygenation of substrates, namely, epoxidation involving singlet oxygen and hydroxylation by superoxy anion. Finally, a detailed explanation of the cytochrome P-450 cycle is discussed, and mechanisms of the different types of oxidative metabolism are presented.

Cytochrome P-450 CYP1A2↗
PubMed1989

Organic nitrate reductase: reassessment of its subcellular localization and tissue distribution and its relationship to the glutathione transferases.

1. Using a specific and sensitive GLC method for the determination of glyceryl trinitrate (GTN), its subcellular and tissue distribution were reassessed. Liver was the most active tissue, but activity was also detected in the heart, kidney and gut. In all tissues activity was localized in the soluble fraction. The activity of soluble glutathione S-transferase followed the same pattern, liver exhibiting the highest and the heart the lowest activity. 2. Pretreatment with phenobarbitone and 3-methylcholanthrene stimulated both the glutathione S-transferase and organic nitrate reductase activities. 3. Glutathione S-transferase activity was competitively inhibited by GTN. 4. A comparison of the plasma and hepatic metabolism of GTN revealed higher drug affinity for the hepatic enzyme.

Animals↗
PubMed1989

The protective effects of L-ascorbic acid and DL-alpha-tocopherol on cultured rat embryos treated with xanthine/xanthine oxidase.

Abnormalities of the neural suture were observed in cultured rat embryos exposed to oxygen radicals generated by xanthine and xanthine oxidase. The distribution of the severity of these abnormalities was altered by the addition of L-ascorbic acid (AA) or DL-alpha-tocopherol (AT). The antioxidant effect of AA and AT were probably responsible for the protection of the embryos from the damaging effects of oxygen radicals.

Animals↗
PubMed1989

Effects of acute and sub-chronic administration of iron nitrilotriacetate in the rat.

Parenteral administration of iron nitrilotriacetate (FeNTA) to rats resulted in marked loss in body weight, and increases in liver/and kidney/body weight ratios. Fatalities, due to renal failure, depended on dosage and age of the animals, and were greater (70%) after a single large dose (12 mg iron) than after repeated smaller doses (30%). FeNTA administered subchronically gave rise to an increase in ethane exhalation, and to decreased liver glutathione peroxidase activity, and decreased cytochrome P-450 concentration and benzphetamine N-demethylase activity. It also resulted in severe renal tubular necrosis, with deposition of iron in the tubular cells and loss of brush border alkaline phosphatase activity, resulting in a dose-dependent diuresis, with increased urinary excretion of glucose, iron and lipid peroxidation products, and decreased urine creatinine concentration. NTA alone had none of these effects but slightly decreased the hepatic concentration of iron.

Acetates↗
PubMed1989

Induction of the rat hepatic microsomal mixed-function oxidases by cimetidine.

The ability of cimetidine to induce the hepatic microsomal mixed-function oxidases was investigated in rats treated orally with the drug at 3 dose levels: 10, 100 and 500 mg/kg. At the highest dose only, cimetidine stimulated the dealkylations of ethoxyresorufin, ethoxycoumarin and pentoxyresorufin but inhibited that of erythromycin and had no effect on the demethylation of dimethylnitrosamine. At the highest dose cimetidine had a small effect on the activation of Glu-P-1 to mutagens in the Ames test but induced proteins recognised in Western blots by antibodies to P450 I A1 and P450 II B1. It is concluded that cimetidine is a weak selective inducer of cytochrome P-450 forms, but at therapeutic doses its inductive effect is most unlikely to be of any clinical or toxicological consequence.

Animals↗
PubMed1989

Prediction of chemical carcinogenicity from molecular and electronic structures: a comparison of MINDO/3 and CNDO/2 molecular orbital methods.

Molecular orbital methods have been used to calculate the electronic structures of a number of chemical carcinogens and non-carcinogens using the MINDO/3 (Modified Intermediate Neglect of Differential Overlap, version 3) and CNDO/2 (Complete Neglect of Differential Overlap) procedures; results from the two methods show good agreement. Spatial conformations of the same series of chemicals have also been determined. High affinity for cytochromes P-448 (P450 I) and high potential for chemical carcinogenicity/toxicity show good correlation with molecular planarity (high values of area/depth2) and low values of the difference between the frontier orbital energies (delta E) of the chemical. This computer graphic procedure identifies substrates of the cytochromes P-448 and is highly suited for the rapid screening of new chemicals for potential mutagenicity, carcinogenicity and certain other forms of toxicity. The implications of these findings to the mechanism of chemical carcinogenicity are discussed.

Carcinogenicity Tests↗
PubMed1988

Decreased expression of cytochrome P-452 in the resistance phenotype characteristic of putative preneoplastic hepatocyte nodules during hepatocarcinogenesis.

Hepatocyte nodules, a characteristic early step in the development of liver cancer in rats, has a distinctive resistance phenotype including a large decrease in total cytochromes P-450 and in two isozymes induced by phenobarbital and two by 3-methylcholanthrene. In this study, it has been observed that the nodules show a large decrease in an additional cytochrome P-450, cytochrome P-452, which is very active in the hydroxylation of lauric acid at C-11 and C-12. The decrease in activity of this microsomal cytochrome P-452 is of the same order of magnitude as the decreases in the other cytochrome P-450 components. These observations are consistent with the hypothesis that there is some more basic alteration in the synthesis or availability of heme and that the changes in the activities of the cytochromes P-450 are secondary.

Aminopyrine N-Demethylase↗
PubMed1988

The induction of autoxidative tissue damage by iron nitrilotriacetate in rats and mice.

Iron nitrilotriacetate (FeNTA) is a potent initiator of lipid peroxidation, and, when injected intraperitoneally into mice, it greatly increased ethane and pentane exhalation within 30 min. The time course and dose-response of the exhalation of ethane were studied and compared with the increase in tissue malondialdehyde (MDA) production. Production of MDA was greater in mouse kidney than liver and correlated better with the exhalation of ethane. In rats FeNTA also increased ethane exhalation and MDA, but the rat was less susceptible than the mouse to FeNTA toxicity. MDA production was greater in rat liver than kidney and both correlated well with ethane exhalation (r = 0.97 and 0.98, respectively). Renal proximal tubular damage was observed histologically 35 min after mice were given FeNTA, but in rats the lesion appeared 24 hr after dosage. Histopathological assessment of kidney damage at these times showed fair correlation with ethane exhalation in mice (r = 0.73) and rats (r = 0.62), respectively. Activities of kidney brush-border marker enzymes were decreased in mice, 35 min after FeNTA administration, and showed a similar trend in rats. Some rats also showed periportal necrosis of the liver, 24 hr after FeNTA administration. The very rapid onset of autoxidative damage suggests that FeNTA itself is the causative agent rather than subsequently formed, less reactive complexes, such as transferrin. The site of damage in the kidney tubule is consistent with the region of concentration of filtered FeNTA. It is suggested that FeNTA supports the formation of superoxide ion from dissolved oxygen and may be responsible for the subsequent formation of hydroxyl radical which initiates lipid peroxidation. The species difference between rat and mouse may be due to the greater resistance of the rat kidney to FeNTA-induced autoxidative damage.

Alkanes↗
PubMed1988

The micro gas-liquid chromatographic analysis of 4-(3',3'-dimethylallyl)-1,2-diphenylpyrazolidine-3,5-dione (feprazone) in human biosamples.

A gas-liquid chromatographic method for the determination of feprazone in various biological matrixes, employing a choice of detector options, is described. After rapid, micro-scale extraction of the sample with n-butyl acetate at physiological pH, the solution was injected directly onto the chromatograph. Separation was with either an OV7 column and flame ionisation or electron capture detection, or with a carbowax high polymer column and nitrogen specific detection. When 100 microl of plasma was extracted the limit of accurate measurement was 2 mg 1(-1) for F.I.D. and N.P.D. and 0.5 mg 1(-1) with E.C. detection. Quantification was by comparison with a range of plasma calibrators carried throughout the procedure, and determination of peak height ratios against an internal standard incorporated into the extracting solvent. The CV of the assay throughout the concentration range normally encountered in patients undergoing feprazone treatment, ranged between 2.4 and 7.8% for the various detector options. The analytical method has been applied to samples collected both from patients and normal volunteers undergoing treatment with a range of feprazone maintenance doses.

Journal Article↗
PubMed1988

Effect of vitamin A on rat hepatic mixed-function oxidases, glutathione transferase activity and generations of oxygen radicals.

Rat hepatic microsomal mixed-function oxidase activities were not significantly affected by vitamin A deficiency. Similarly cytosolic glutathione S-transferase and glutathione reductase activities as well as total glutathione levels were unaffected by the vitamin A status. Induction of the mixed-function oxidases by 3-methylcholanthrene or phenobarbitone was independent of the vitamin A status. No significant differences in microsomal chemiluminescence, before and following challenge with tertiary butyl hydroperoxide, were evident between the vitamin-A-deficient animals and those maintained on vitamin-A-supplemented diets. The present findings indicate that the protective action of vitamin A against chemical carcinogens is unlikely to involve modulation of the enzyme systems responsible for their metabolism.

Animals↗
PubMed1988

Metabolic activation of carcinogens and toxic chemicals.

1. The spatial parameters and electronic structures of 100 exogenous and endogenous chemicals have been determined by computer graphics, from which their oxidative metabolism by the cytochrome P-448 (activation) or the other families of cytochromes P-450 (generally detoxication) have been predicted. 2. The spatial parameters of these chemicals primarily determine the family of cytochrome P-450 by which the chemicals are metabolized and the electronic structures primarily determine their ease of oxidative metabolism. 3. The role of oxidative metabolism of xenobiotics by the cytochromes P-448, and their binding to the cytosolic Ah receptor, are considered in relationship to the mechanisms of chemical toxicity, mutagenicity, carcinogenicity, and co-carcinogenicity. 4. The mechanisms of chemical toxicity and carcinogenesis are considered in respect of activation through cytochrome P-448-mediated, conformationally-hindered oxygenation to reactive intermediates which, unlike most cytochrome P-450-oxygenated metabolites, are not acceptable substrates for conjugation and detoxication and therefore react with essential intracellular macromolecules. 5. The computer graphic method of determining the molecular conformations and electronic structures of molecules is a rapid, scientifically-based procedure for evaluation of the potential toxicity, mutagenicity and carcinogenicity of chemicals.

Biotransformation↗
PubMed1988

The disposition of feprazone and its hydroxylated metabolite in human volunteers.

1. 14C-Feprazone administered as a single oral dose (17 mg/subject) to each of 3 human volunteers on the 6th day of repeated dosage with unlabelled feprazone (200 mg/subject, twice daily) was excreted slowly, with only 19-38% of the dose excreted in the urine in 8 days, with a further 27-49% of the dose in the faeces. 2. 14C-Feprazone had a half-life of 30-33 h, similar to that after single dosage of unlabelled feprazone (22-33 h). The half-life for total 14C was not significantly different from that for unchanged feprazone, indicating that no metabolite with a very long half-life was formed. 3. Only feprazone and 4'-hydroxyfeprazone were detected in the plasma of subjects dosed orally with feprazone, the metabolite being characterized by mass spectrometry. The time of peak plasma concentration of feprazone was 4-5 h after dosage, and of 4'-hydroxyfeprazone was approx. 25 h. The urine contained feprazone plus its C-glucuronide, and 4'-hydroxyfeprazone plus its conjugate (glucuronide), in the ratio of approx. 5:1. 4. When 4'-hydroxyfeprazone was administered as a single oral dose to a human volunteer the plasma elimination half-life of the metabolite was 18 h, but after administration of feprazone the half-life of 4'-hydroxyfeprazone was 45 +/- 29 h (10 subjects), indicating the slow hydroxylation of feprazone and the slow excretion of 4'-hydroxyfeprazone. The clearance of feprazone was 5.2 and of 4'-hydroxyfeprazone was 5.5 ml/kg/h. 5. These studies have shown that even though enterohepatic recirculation of the drug in man is indicated, the plasma half-life of feprazone is unchanged on repeated dosage, and accumulation of the drug at a daily dosage of 2 x 200 mg, does not occur.

Carbon Radioisotopes↗