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Biomedical subjects

C F Wilkinson

Publications and source records attributed to C F Wilkinson.

At least 37 records · Page 2Linked to original sources
PubMed1983

Effects of dihydrosafrole on cytochromes P-450 and drug oxidation in hepatic microsomes from control and induced rats.

Changes in cytochromes P-450, aminopyrine N-demethylase (APDM), aromatic hydrocarbon (benzo[a]pyrene) hydroxylase (AHH), and type III spectral complex formation were measured in hepatic microsomes of control, phenobarbital (PB)-, and beta-naphthoflavone (beta NF)-induced rats after a single dose of dihydrosafrole (4-n-propyl-1,2-methylenedioxybenzene, DHS). Time profiles of changes in these microsomal parameters were complex and showed that APDM activities and cytochrome P-450 levels decreased immediately after treatment and were associated with concurrent increases in the intensity of the type III methylenedioxyphenyl (MDP) metabolite/cytochrome P-450 spectral complex. In noninduced rats, both APDM activity and cytochrome P-450 levels returned to control levels between 12 and 24 hr after treatment with DHS and subsequently increased above control levels. In PB- and beta NF-induced animals, the inhibitory phases were more prolonged and activity never returned to levels higher than the corresponding controls. AHH activity was increased substantially (two- to three-fold) in all cases after DHS administration. Although displacement of the MDP metabolite/cytochrome P-450 complex with 2-methylbenzimidazole generally led to a marked restoration of cytochrome P-450 levels and partially reversed the inhibition of APDM, it had little or no effect on AHH activities.

Aminopyrine N-Demethylase↗
PubMed1983

Selectivity of 1-phenylimidazole as a ligand for cytochrome P-450 and as an inhibitor of microsomal oxidation.

Equilibrium dialysis studies established that 1-[4'-(3H)-phenyl]imidazole (PI) was bound to hepatic microsomal suspensions from control, phenobarbital (PB)- and 3-methylcholanthrene (3MC)-treated rats and that the binding was directly related to the cytochrome P-450 content. Computer-assisted Scatchard plot analysis of the binding data indicated the existence of two major types of microsomal binding sites in both control and induced rats, one with a high affinity (Ka approximately 1.5 X 10(7) M-1) and the other with a low affinity (Ka approximately 5 X 10(5) M-1) for PI. The binding of PI to the highly purified, individual cytochrome P-450s that constituted the major forms from the PB- and beta-naphthoflavone (beta NF)-induced rats exhibited affinities similar to the high and low affinity binding sites observed in microsomal suspensions. The two types of PI binding sites were characteristic of two classes of cytochrome P-450, and the major cytochrome induced by PB and 3MC (or beta NF) were each associated with one of these two classes. In concurrence with this, it was shown that, although PI was an excellent inhibitor of aromatic hydrocarbon hydroxylase (AHH) activity in PB-induced rats, it exhibited little or no inhibitory activity towards AHH activity in 3MC-induced animals.

Animals↗
PubMed1983

Structure-activity relationships in the interactions of alkoxymethylenedioxybenzene derivatives with rat hepatic microsomal mixed-function oxidases in vivo.

Following in vivo administration to rats of equimolar amounts of a series of 4-n-alkoxymethylenedioxybenzene (AMDB) derivatives, hepatic microsomal aryl hydrocarbon hydroxylase (AHH) activities, total cytochrome P-450 levels, and AMDB metabolite-cytochrome P-450 spectral complex (455 nm) formation were well correlated in parabolic relationships with pi, the hydrophobic constant of the n-alkoxy substituent. Each of these parameters increased progressively over control values with increasing carbon chain length of the alkoxy substituent, passed through an optimal value in compounds containing five or six carbon atoms, and subsequently decreased with the higher homologues. AHH activity was highly correlated in linear relationships with total (complexed plus uncomplexed) cytochrome P-450 content and intensity of the 455-nm spectral complex. Aminopyrine N-demethylase activities in microsomes from AMDB-treated rats were not well correlated with cytochrome P-450 levels or spectral complex formation. AMDB metabolite-ferricytochrome P-450 complexes varied considerably in their relative ease of displacement following treatment with 2-n-heptylbenzimidazole, those derived from the n-butoxy to n-hexoxy derivatives being particularly stable toward the displacer. The results are discussed in relation to the possible mechanisms involved in the interactions of methylenedioxyphenyl compounds with cytochrome P-450 and drug oxidation.

Animals↗
PubMed1979

Purification and characterization of NADPH--cytochrome c reductase from the midgut of the southern armyworm (Spodoptera eridania).

1. NADPH-cytochrome c reductase was solubilized with bromelain and purified about 400-fold from sucrose/pyrophosphate-washed microsomal fractions from southern armyworm (Spodoptera eridania) larval midguts. 2. The enzyme has a mol.wt. of 70 035 +/- 1300 and contained 2 mol of flavin/mol of enzyme consisting of almost equimolar amounts of FMN and FAD. 3. Aerobic titration of the enzyme with NADPH caused the formation of a stable half-reduced state at 0.5 mol of NADPH/mol of flavin. 4. Kinetic analysis showed that the reduction of cytochrome c proceeded by a Bi Bi Ping Pong mechanism. 5. Apparent Km values for NADPH and cytochrome c and Ki values for NADP+ and 2'-AMP were considerably higher for the insect reductase than for the mammalian liver enzyme. 6. These are discussed in relation to possible differences in the active sites of the enzymes.

Adenosine Monophosphate↗
PubMed1977

Insecticide solvents: interference with insecticidal action.

Several commercial solvent mixtures commonly used as insecticide carriers in spray formulations increase by more than threefold the microsomal N-demethylation of p-chloro N-methylaniline in midgut preparations of southern army-worm (Spodoptera eridania) larvae exposed orally to the test solvents. Under laboratory conditions, the same solvent mixtures exhibit a protective action against the in vivo toxicity of the insecticide carbaryl to the larvae. The data are discussed with respect to possible solvent-insecticide interactions occurring under field conditions and, more broadly, to potential toxicological hazards of these solvents to humans.

Enzyme Induction↗
PubMed1975

Properties of 5-aminolaevulinate synthetase and its relationship to microsomal mixed-function oxidation in the southern armyworm (Spodoptera eridania).

1. Activity of 5-aminolaevulinate synthetase was measured in the midgut and other tissues of the last larval instar of the southern armyworm (Spodoptera eridania Cramer, formerly Prodenia eridania Cramer). 2. Optimum conditions for measuring the activity were established with respect to all variables involved and considerable differences from those reported for mammalian enzyme preparations were found. 3. Maximum activity (20 nmol/h per mg of protein) occurs 18-24 h after the fifth moult and thereafter decreases to trace amounts as the larvae age and approach pupation. 4. Synthetase activity was rapidly induced by oral administration (in the diet) of pentamethylbenzene, phenobarbital, diethyl 1,4-dihydro-2,4,6-trimethylpyridine-3, 5-dicarboxylate, and 2-allyl-2-isopropylacetamide. 5. Puromycin inhibited the induction of synthetase by pentamethylbenzene. 6. Induction of 5-aminolaevulinate synthetase correlated well with the induction of microsomal N-demethylation of p-chloro-N-methylaniline, except for phenobarbital, which induced the microsomal oxidase relatively more than the synthetase.

5-Aminolevulinate Synthetase↗