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Results for “Benzhydryl Compounds”

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PubMed1989

Effects of mutagenic and non-mutagenic aniline derivatives on rat liver drug-metabolizing enzymes.

1. The effect of 4,4'-methylene bis(2-chloroaniline) (MOCA), 4,4'-methylene dianiline (MDA) and 4,4'-sulphonyldianiline (Dapsone) in vivo on xenobiotic biotransformation in male rat liver was studied. 2. Treatment with MOCA or MDA but not Dapsone caused a dose-dependent increase in ethoxyresorufin O-deethylase activity and a concomitant decrease in aldrin epoxidase activity in male rats. 3. Treatment with MOCA or MDA resulted in dose-dependent increases in ethoxycoumarin O-deethylation and epoxide hydrolation, while only MOCA induced cytosolic glutathione S-transferase activity. 4. Treatment with Dapsone resulted in no changes in xenobiotic biotransformation except for the induction of aniline hydroxylation. 5. The results are consistent with the contention that there is a relationship between carcinogenic chemicals and particular alterations in the activities of biotransformation enzymes.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

[Effect of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate in the presence of succinate].

The effects of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate were examined. Idebenone inhibited lipoperoxide (LPO) production in brain homogenate in a concentration-dependent manner, with an IC50 of 38 microM. The inhibition was strongly enhanced (about 100-fold) by adding succinate, a substrate in the mitochondrial respiration. The optimal concentration of succinate was 0.5 mM. Inhibition of lipid peroxidation in brain homogenate by various nootropic drugs in the presence or absence of succinate was then examined. Drugs added to the brain homogenate at 100 microM in the absence of succinate inhibited LPO production in the order: idebenone greater than vinpocetine greater than bifemelane greater than indeloxazine greater than calcium hopantenate. However, when the drugs were added at 1 microM in the presence of succinate, only idebenone demonstrated inhibition. These results suggest that although almost all of the drugs tested inhibit lipid peroxidation in brain homogenate, only idebenone is activated by succinate, the other drugs being insensitive to this compound.

Animals↗
PubMed1989

Significant changes in nonspecific bronchial responsiveness after isolated immediate bronchospecific reactions caused by isocyanates but not after a late reaction caused by plicatic acid.

Although late bronchospastic reactions after exposure to antigenic and sensitizing agents usually significantly alter bronchial responsiveness to histamine or methacholine, presumably by causing bronchial inflammation, isolated immediate bronchospastic reactions do not induce such changes. We studied three subjects who demonstrated different patterns of reaction. The first individual was diagnosed as having occupational asthma to red cedar. This was confirmed by specific inhalation challenges that resulted in late bronchospastic reaction. No significant changes in the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) were found 1 day after this reaction. Two weeks later, serial assessments (five and six, respectively) of PC20 histamine were recorded on control days and up to 48 hours after exposure to plicatic acid, which caused a late bronchospastic reaction with a maximum fall of 37% in FEV1. No significant changes in PC20 were found; the maximum variations on control days were 0.36 to 0.74 mg/ml, and on active days, from 0.37 to 0.59 mg/ml. By contrast, two other subjects, who demonstrated isolated immediate reactions after exposure to diphenylmethane diisocyanate, had significant changes in PC20 histamine and methacholine, in one subject from 3.1 mg/ml to 0.6 mg/ml 8 hours after exposure, and in the other subject, from 61.0 to 7.4 mg/ml 7 hours after exposure, with recovery during the next few days. These examples demonstrate that the pattern of nonspecific bronchial responsiveness after immediate and late bronchospastic reactions can be different from what has previously been described. Immediate bronchospastic reactions may lead to bronchial hyperresponsiveness, whereas late asthmatic reactions do not always induce changes in bronchial responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1999

UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation.

1. UK-78,282, a novel piperidine blocker of the T lymphocyte voltage-gated K+ channel, Kv1.3, was discovered by screening a large compound file using a high-throughput 86Rb efflux assay. This compound blocks Kv1.3 with a IC50 of approximately 200 nM and 1:1 stoichiometry. A closely related compound, CP-190,325, containing a benzyl moiety in place of the benzhydryl in UK-78,282, is significantly less potent. 2 Three lines of evidence indicate that UK-78,282 inhibits Kv1.3 in a use-dependent manner by preferentially blocking and binding to the C-type inactivated state of the channel. Increasing the fraction of inactivated channels by holding the membrane potential at - 50 mV enhances the channel's sensitivity to UK-78,282. Decreasing the number of inactivated channels by exposure to approximately 160 mM external K+ decreases the sensitivity to UK-78,282. Mutations that alter the rate of C-type inactivation also change the channel's sensitivity to UK-78,282 and there is a direct correlation between tau(h) and IC50 values. 3. Competition experiments suggest that UK-78,282 binds to residues at the inner surface of the channel overlapping the site of action of verapamil. Internal tetraethylammonium and external charybdotoxin do not compete UK-78,282's action on the channel. 4. UK-78,282 displays marked selectivity for Kv1.3 over several other closely related K+ channels, the only exception being the rapidly inactivating voltage-gated K+ channel, Kv1.4. 5. UK-78,282 effectively suppresses human T-lymphocyte activation.

Animals↗
PubMed1986

Sensitizing capacity of dihydroxydiphenyl methane (bisphenol F) in the guinea pig.

The sensitizing capacity of 2,2(1)-dihydroxydiphenyl methane (2,2(1)-HPM), 4,4(1)-dihydroxydiphenyl methane (4,4(1)-HPM) and 2,4(1)-dihydroxydiphenyl methane (2,4(1)-HPM) was investigated with the guinea pig maximization test. These compounds are known contact sensitizers in phenol-formaldehyde resins. The study was performed to assess and compare their sensitizing capacities. A weak sensitizing capacity of 2,2(1)-HPM was demonstrated when the results for 2 separate series were added, while no sensitizing capacity was demonstrated for 4,4(1)-HPM or 2,4(1)-HPM. The compounds tested were chromatographically pure.

Animals↗
PubMed1991

Occupational skin diseases from epoxy compounds. Epoxy resin compounds, epoxy acrylates and 2,3-epoxypropyl trimethyl ammonium chloride.

Of a total of 3731 patients investigated between 1974 and 1990, 1844 (49.4%) had an occupational skin disease. Of them 142 (7.7%) had an occupational skin disease caused by epoxy compounds--135 patients (95%) had allergic contact dermatitis, five had irritant contact dermatitis, and two had contact urticaria. Apart from dermatoses, two patients had IgE-mediated asthma from exposure to DGEBA epoxy resins. Thus epoxy compounds are one of the main causes of occupational allergic contact dermatoses and can be considered potential causes of occupational asthma. The most frequent causes were epoxy resin compounds, which together induced 93% (132 cases) of all epoxy compound dermatoses. The three most common causative products were epoxy paints and their raw materials (31%, 41 cases), epoxy resin compounds used in electrical insulation (29%, 38 cases) and epoxy glues (18%, 24 cases). Fewer cases were caused by products containing epoxy acrylate and EPTMAC. The present study found that, in addition to contact allergy to DGEBA epoxy resins, contact allergy to epoxy hardeners, non-DGEBA resins and reactive diluents is common. Polyamine hardeners, most frequently MDA, DETA and TETA, rarely IPDA, tris-DMP, EDA, TMD and XDA, were the second commonest causes of contact allergy induced by epoxy resin compounds, after DGEBA epoxy resins. Cycloaliphatic epoxy resins and other non-DGEBA epoxy resins, including heterocyclic dimethyl hydantoin, phenol novolak and brominated epoxy resins, were the third commonest causes, and reactive diluents the fourth commonest cause of allergic dermatitis due to epoxy resin compounds. Most patients sensitized to reactive diluents were allergic to PGE, ortho-CGE, HDDGE and BDDGE, whereas fewer patients were sensitized to AGE, NPGDGE and BGE. Cross-sensitization between reactive diluents was common. Cardura E 10 and Epoxide 8 provoked no reactions. The present study also indicated that DGEBA epoxy resins with a high average MW ought to be regarded as potential sensitizers, and organic solvents probably promote sensitization to DGEBA, even if the amount of DGEBA is low in the causative products. When contact dermatitis induced by epoxy compounds is suspected, an accurate diagnosis is made with the use of detailed data on the patient's exposure and extensive patch testing, including tests with the patient's own products. No chemical can be used alone to screen for sensitization to all different contact allergens of epoxy compounds.(ABSTRACT TRUNCATED AT 400 WORDS)

Benzhydryl Compounds↗
PubMed2004

Computational modeling of serum-binding proteins and clearance in extrapolations across life stages and species for endocrine active compounds.

One measure of the potency of compounds that lead to the effects through ligand-dependent gene transcription is the relative affinity for the critical receptor. Endocrine active compounds that are presumed to act principally through binding to the estrogen receptor (e.g., estradiol, genistein, bisphenol A, and octylphenol) comprise one class of such compounds. For making simple comparisons, receptor-binding affinity has been equated to in vivo potency, which consequently defines the dose-response characteristics for the compound. Direct extrapolation of in vitro estimated affinities to the corresponding in vivo system and to specific species or life stages (e.g., neonatal, pregnancy) can be misleading. Accurate comparison of the potency of endocrine active compounds requires characterization of biochemical and pharmacokinetic factors that affect their free concentration. Quantitative in vitro and in vivo models were developed for integrating pharmacokinetics factors (e.g., serum protein and receptor-binding affinities, clearance) that affect potency. Data for parameterizing these models for several estrogenic compounds were evaluated and the models exercised. While simulations of adult human or rat sera were generally successful, difficulties in describing early life stages were identified. Exogenous compounds were predicted to be largely ineffective at competing estradiol off serum-binding proteins, suggesting this was unlikely to be physiologically significant. Discrepancies were identified between relative potencies based upon modeling in vitro receptor-binding activity versus in vivo activity in the presence of clearance and serum-binding proteins. The examples illustrate the utility of this approach for integrating available experimental data from in vitro and in vivo studies to estimate the relative potency of these compounds.

Adult↗
PubMed1986

Sensitizing capacity of 4,4(1)-dihydroxy-(hydroxymethyl)-diphenyl methanes in the guinea pig.

The sensitizing capacity of 4,4(1)-dihydroxy-3-(hydroxymethyl)-diphenyl methane (4,4(1)-H-3-HPM), 4,4(1)-dihydroxy-3,3(1)-di-(hydroxymethyl)-diphenyl methane 4,4(1)-H-3,3(1)--HPM) and 4,4(1)-dihydroxy-3,5-di-(hydroxymethyl)-diphenyl methane (4,4(1)-H-3,5-HPM) was investigated using the guinea pig maximization text. These compounds are known contact sensitizers in phenol-formaldehyde resins (P-F-R). The study was performed in order to assess and compare the degrees of the sensitizing capacities of these chemically related substances. The animals were also rechallenged with the sensitizer and 5 related compounds, all known to be present in P-F-R, in order to study the cross-reaction patterns. 4,4(1)-H-3,3(1)-HPM was demonstrated to be a strong sensitizer and 4,4(1)-H-3-HPM and 4,4(1)-H-3,5-HPM to be moderate sensitizers. With 4,4(1)-H-3,3(1)-HPM as the sensitizer, 4,4(1)-H-3-HPM and 4,4(1)-H-3,5-HPM were cross-reacting substances and simple methylol phenols were possible cross-reacting compounds. Possible cross-reactivity were indicated between the three 4,4(1)-H-HPM when 4,4(1)-H-3-HPM and 4,4(1)-H-3,5-HPM respectively were the sensitizers. The chemical investigation by high pressure liquid chromatography indicated that the compounds tested were pure and separable.

Animals↗
PubMed1986

Absence of hyperresponsiveness to methacholine in a worker with methylene diphenyl diisocyanate (MDI)-induced asthma.

A 29-year-old man had a persuasive history of respiratory illness following exposures to methylene diphenyl diisocyanate (MDI). He was evaluated by measuring bronchial reactivity to methacholine, both before and after controlled laboratory exposures to MDI. Despite evidence of progressive declines in FEV1 with increasing (but subirritant) doses of MDI on three consecutive days, there was no bronchial hyperresponsiveness to methacholine, before or after MDI challenge. We conclude that the absence of nonspecific bronchial hyperresponsiveness does not exclude the possibility of isocyanate asthma. In the face of a compelling history, a negative result of methacholine challenge should not deter observation or laboratory testing for specific respiratory allergy to these chemicals.

Adult↗