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Biomedical subjects

J Jacob

Publications and source records attributed to J Jacob.

At least 199 records · Page 11Linked to original sources
PubMed1983

Benzo[e]pyrene metabolism in rat liver microsomes: dependence of the metabolite profile on the pretreatment of rats with various monooxygenase inducers.

Benzo[r]pyrene (B[e]P) is metabolized by liver microsomes of untreated rats to trans-4,5-dihydroxy-4,5-dihydrobenzo(e)pyrene and 1- as well as 3-hydroxybenzo[e]pyrene as shown by g.l.c. and mass spectrometry of their trimethylsilyl ethers. After pretreatment of the rats with various monooxygenase inducers oxidation at the 9/10-position was also observed. In addition, secondary oxidation to dihydrodiolepoxides and the formation of a tetrol, tentatively identified as 4,5,9,10-tetrahydroxy-4,5,9,10-tetrahydrobenzo[e]pyrene was detected after incubation of B[e]P with liver microsomes of rats treated with polycyclic aromatic hydrocarbons. However, no formation of the supposed ultimate carcinogen, the 9,10-dihydroxy-11,12-epoxy-9,10,11,12-tetrahydrobenzo[e]pyrene could be observed after any of the pretreatments.

Animals↗
PubMed1982

Hyperalgesia induced by non-noxious stress in the rat.

Stress-induced analgesia is well known but the reverse phenomenon is poorly documented. In this work, hyperalgesia is described following stressful but non-noxious manipulations consisting of inescapable holding or exposure to a novel environment. Hypophysectomy (HX) and dexamethasone enhanced 'holding' hyperalgesia. In contrast, 'novelty' hyperalgesia was reduced by HX and not modified by dexamethasone. So, pituitary factors may respectively compensate and take part in stress hyperalgesia. Thus pain can be modulated in opposite directions by different types of stimulation: hyperalgesia would predominate after moderate, anxiogenic stress and analgesia after noxious and/or intense stress.

Animals↗
PubMed1982

The effect of pituitary removal on pain regulation in the rat.

The effects of hypophysectomy (HX) on pain regulation in basal and in various stressful situations were investigated in the rat. Pain sensitivity was assessed by measuring the thresholds of 3 nociceptive reactions (tail withdrawal, vocalization, vocalization afterdischarge) following electrical stimulation of the tail. The completeness of HX and the integrity of hypothalamus were verified in each HX rat. (1) Baseline pain thresholds were lower in HX rats than in sham-operated animals; (2) naloxone (Nx) hyperalgesia was only slightly altered by HX; (3) different types of stress induced different types of changes in nociception i.e. analgesia or hyperalgesia. The influence of HX varied according to the stress: it increased hyperalgesia, reduced analgesia, or had no effect at all. These results indicate that in the rat: (i) the pituitary participates in the regulation of basal pain sensitivity, probably through analgesic factors; (ii) Nx hyperalgesia results essentially from an antagonism of endogenous opioids originating in the CNS and not in the pituitary; and (iii) the pain regulatory processes engaged in adaptation to stressful stimuli involve the CNS and the pituitary in variable proportions depending upon the nature of the stress.

Animals↗
PubMed1982

Observations on the ultrastructure of human urothelium: the response of normal bladder of elderly subjects to hyperthermia.

An electron microscopic study of normal bladder urothelium of elderly subjects treated by hyperthermic perfusions has shown that the tissue responds, sooner or later, in every instance by desquamation. There is no evidence of cell death prior to desquamation although various organelles undergo structural alterations. Mitochondria are especially prone to suffer varying degrees of damage. A short heat shock has revealed differences in the initial response of the thick and thin regions of bladder urothelium known to occur in elderly subjects. After a long, fractionated treatment, regeneration is evident within 3 days of the end of treatment, and follow-up biopsies have revealed a hyperplastic urothelium within 10 to 12 weeks. The constituent cells show signs of cytodifferentiation at this time but it remains unknown when an ultrastructurally normal urothelium with characteristic cell layers will be restored. The various treatments in this study suggest that the stem cells in the epithelium are unaffected by the levels of hyperthermia employed and that their unimpaired proliferative capacity ensures regeneration of the urothelium.

Aged↗
PubMed1982

Cis-platinum and 5-fluorouracil as induction therapy for advanced head and neck cancer.

Sixty-one patients were treated with a three course induction regimen of 5-fluorouracil and cis-platinum for advanced squamous cell carcinoma of the head and neck area. Thirty-three patients (54 percent) had complete clinical remission with the administration of these drugs. Twenty-four patients (39 percent) showed a 50 percent or greater reduction in tumor size, for a significant response rate of 93 percent. The toxicities were within acceptable limits, and only three patients did not complete all three courses. Surgery and radiation therapy were supposed to follow the chemotherapy but several patients refused surgery after the disappearance of their lesion. This has created a problem in patient management.

Carcinoma, Squamous Cell↗
PubMed1982

Influence of monooxygenase inducers on the metabolic profile of phenanthrene in rat liver microsomes.

The oxidation of phenanthrene by rat liver microsomes significantly depends on the pretreatment of the animals as shown by means of gas chromatography/mass spectrometry. Whereas untreated animals convert phenanthrene exclusively into the 9,10-dihydrodiol (K-region), pretreatment with various polycyclic aromatic hydrocarbons and related compounds resulted in different rates of additional oxidation at the 1,2- and 3,4-position. Moreover, secondary metabolism to dihydrodiol epoxides, detected as triols, was observed. Despite considerable concentration of the proximate carcinogen of phenanthrene (1,2-dihydrodiol) only low concentrations of the ultimate carcinogen were detected which may explain the carcinogenic inefficiency of this hydrocarbon.

Animals↗
PubMed1982

On the metabolic activation of benz[a]acridine and benz[c]acridine by rat liver and lung microsomes.

The metabolism of benz[a]- and benz[c]acridine by liver and lung microsomes from untreated, phenobarbital (PB)-treated and benzo[k]fluoranthene (BkF)-treated rats has been studied by gas chromatography/mass spectrometry (GC/MS). Epoxidation and hydrolysis of the epoxides to dihydrodiols were found to be the predominant pathways for all substrates. N-Oxidation is likely to occur in the case of benz[c]acridine. However, no unequivocal evidence could be obtained for the formation of the ultimate carcinogens--the t-3,4-dihydrodiol-1,2-epoxides--in case of both benz[a]- and benz[c]acridine. K-Region oxidation was induced by phenobarbital, whereas the formation of non-K-region metabolites increased after BkF treatment in the case of benz[c]acridine.

Acridines↗
PubMed1982

The metabolism of pyrene by rat liver microsomes and the influence of various mono-oxygenase inducers.

1. Pyrene metabolite g.l.c. profiles were recorded and metabolites identified by mass spectrometry. 2. Pyrene is metabolized by liver microsomes of untreated rats to 1-hydroxypyrene, 4,5-dihydroxy-4,5-dihydropyrene, two different diphenols and a triol, tentatively identified as 1,4,5-trihydroxy-4,5-dihydropyrene. 3. Pretreatment with phenobarbital or polychlorinated biphenyls favours oxidation at the K-region, whereas cytochrome P-448 inducers stimulate oxidation at the non-K-region of pyrene. 4. 1-Hydroxypyrene does not inhibit pyrene oxidation. 5. Pyrene diphenols are formed by secondary oxidation of 1-hydroxypyrene. 6. Triols are formed from dihydrodiols by secondary oxidation.

Animals↗
PubMed1981

Endogenous morphines and pain.

The involvement of endogenous morphines (enkephalins and endorphins) in the regulation of pain is demonstrated by the following experimental evidence: (a) their analgesic activities; (b) their distribution in the central nervous systems; (c) the effects of their modifiers, especially of their antagonists, on nociceptive reactions and (or) on various types of analgesia; (d) rare modifications of their brain levels in pain and (or) analgesic states. Besides the well-known facts, the following items are particularly stressed: the functional roles of hypothalamic structures and of the pituitary, the effects of antagonists, the variety of analgesia following noxious and (or) stressful stimuli, genetic and environmental factors, endogenous antinociceptive substances other than opioids, relations with biogenic amines. As a whole, endogenous morphines apparently filter the particular important sensory input represented by nociception and control the reactions to pain, allowing for adjusted behaviour, if the stimuli are avoidable, or for prevention or at least delay of exhaustion if the stimuli are unavoidable.

Animals↗
PubMed1981

Dose-dependent induction of rat liver microsomal aryl hydrocarbon monooxygenase by benzo[k]fluoranthene.

The environmentally widespread polycyclic aromatic hydrocarbon (PAH) benzo[k]fluoranthene is a potent AHH inducer. This has been proven by recording the benz[a]anthracene metabolite profile in the rat liver by means of gas chromatography/mass spectrometry (GC/MS) technique. Even a total dose of 3 times 50 micrograms/kg body wt increases the metabolism of benz[a]anthracene by a factor of 2. The formation of the 8,9- as well as the 5,6-dihydrodiol is stimulated to about the same extent, whereas the formation of the 10,11-dihydrodiol is suppressed. After comparatively low doses of the inducer, a metabolite is formed which corresponds in all parameters with the postulated ultimate carcinogen 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene. This metabolite and a number of other primary and secondary oxidation products could be identified after incubation with induced but not with normal microsomes. Therefore, it should be emphasised that metabolite profiles have to be recorded instead of measuring brutto conversions of PAH substrates to evaluate inducing effects.

Animals↗
PubMed1981

The influence of polycyclic aromatic hydrocarbons as inducers of monooxygenases on the metabolite profile of benz[a]anthracene in rat liver microsomes.

Microsomal oxidation of benz[a]anthracene (BaA) in rat liver has been shown to occur at various positions (1,2-, 3,4-, 5,6-, 8,9- and 10,11-position) by means of gas chromatography/mass spectrometry (GC/MS) and comparison with synthetic reference substances. In normal rats trans-5,6-, 8,9- and, mainly, 10,11-dihydrodiols have been detected as primary metabolites. The induction of monooxygenases by polycyclic aromatic hydrocarbon (PAH) results in a considerable change in the metabolite profile, since the 5,6- and 8,9-isomers become the main metabolites while the amount of 10,11-isomer is not increased. Simultaneously, the secondary metabolism to form triols and tetrols is induced. Phenobarbital as well as 'moderately inducing' PAH (pyrene, benzo[ghi]perylene, benzo[e]pyrene) induced the oxidation at 5,6- and 8,9-position, whereas almost all other compounds investigated, especially the benzofluoranthenes, additionally induced the oxidation at the 3,4-position forming the precursor of the ultimate carcinogen of BaA, 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene, which was detected as its isomerisation product, the 2,3,4-triol.

Animals↗
PubMed1981

Time course of oxidative benz[a]anthracene metabolism by liver microsomes of normal and PCB-treated rats.

The time course for the oxidative metabolism of benz[a]anthracene by liver microsomes of normal, 3,3',4,4'-tetrachlorobiphenyl-(TCBP) and polychlorinated biphenyl-(PCB) treated rats has been investigated. These are shown not to be linear in all cases. In normal microsomes the 10,11-dihydrodiol is the main metabolite, followed by the 5,6- and 8,9-dihydrodiols. Secondary metabolism, i.e. formation of dihydrodiol epoxides, is observed only after 5 min. In contrast, TCBP microsomes produced predominantly the 5,6-dihydrodiol followed by the 8,9-dihydrodiol, whereas the formation of the 10,11-dihydrodiol is suppressed. Metabolism deriving from oxidation of the 5,6-position is increased 15-20 fold; again secondary metabolites occur between the 5th and 10th min of incubation. Gas chromatography and mass spectra data suggests the formation of the ultimate carcinogen, 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene, as concluded from detection of its rearrangement product, the 2,3,4-triol. In PCB-treated rats secondary metabolism is observed within 2.5 min. 5,6-Oxidation is increased 27 fold, 8,9-oxidation 10 fold, but 10,11-oxidation is completely suppressed. The above-mentioned ultimate carcinogen is also formed. Moreover, a series of tetrols is detected. Optimum incubation times dependent on the problem under study are discussed.

Animals↗
PubMed1981

Glass-capillary-gas chromatography/mass spectrometry data of mono- and polyhydroxylated benz[a]anthracene. Comparison with benz[a]anthracene metabolites from rat liver microsomes.

By means of glass-capillary-gas chromatography all possible benz[a]anthracene metabolites formed by rat liver microsomes (phenols, dihydrodiols, dihydrodiol enols and tetrahydrotetrols) can be separated. Mass spectra of their trimethylsilyl ethers show intense molecule ions and, in most cases, characteristic fragments. K-Region diols and their secondary oxidation products can be recognized by the ratio (m/e 147) (m/e 191) greater than 1, whereas the ratio is inverse in all other dihydrodiol trimethylsilyl ethers investigated. With the exception of 1,2-dihydrobenz[a]anthracene-1,2,3-triol all vicinal dihydrodiol enols investigated exhibit an intense elimination of the fragment CH = CH-OSiMe3 according to m/e 379. The conformation of vicinal tetrahydrobenz[a]anthracenetetrols possibly can be distinguished by the intensity of m/e 380 (M - 240) since only in those possessing two or more subsequent Me3SiO groups in the same conformation intense elimination of Me3Si-O-CH = CH-O-SiMe3 is observed. Retention times and mass spectrometric data of a series of synthetic benz[a]anthracene derivatives are presented as a base for the identification of benz[a]anthracene metabolites in biological systems.

Animals↗
PubMed1980

The effect of medial hypothalamus lesions on pain control.

In the rat, discrete electrolytic lesions located in 6 different parts of the medial hypothalamus (MH) are shown to induce clearcut hyperalgesia. During a time limit of 14 days following the lesions, no other obvious deficits were noticed (in sensory and/or motor functions, affectivity towards conspecifics, food and water intake). Three nociceptive reactions (tail withdrawal, vocalization, vocalization after-discharge) were tested and their thresholds measured following electrical stimulation of the tail. The lesions aimed at the rostral part of the arcuate nucleus, as well as at ventromedial and dorsomedial nuclei, produced the most profound hyperalgesia. The possible involvement of the endorphinergic and enkephalinergic systems known to be located in the MH is discussed. The relation between the hyperalgesic effects of MH lesions and various structures (limbic areas, descending pain control system, pituitary) is also considered.

Animals↗
PubMed1980

[3H]5-HT binding sites and 5-HT-sensitive adenylate cyclase in glial cell membrane fraction.

Glial cell membrane fractions were prepared using glial cells preparations isolated from horse brain striatum. [3H]5-HT binding was measured by the filtration technique and the adenylate cyclase activity determined by measuring the cAMP production using a radioimmunoassay. Serotonin binds to glial membrane fractions with an affinity corresponding to a dissociation constant Kd = nM. The corresponding site is serotoninergic specific: [3H]5-HT binding is inhibited by 5-HT agonists (5 OH NM-DMT, 5-MeOHT, 5-MeOH-DMT, NN-DMT) or antagonists (cinanserine, cyproheptadine, methysergide, LSD) and not (or poorly) inhibited by non-serotoninergic related drugs. The population of sites binding 5-HT, present in neuronal membrane preparations and determined in parallel assays is distinct from that observed in glial preparations. The glial membrane fractions contains an adenylate cyclase activated by 5-HT with an apparent affinity constant close to 1 microM. It is serotonin-specific and clearly distinct from the DA-stimulated adenylate cyclase present in the same preparation. The sites binding 5-HT and activating the adenylate cyclase with low affinities might be directly related. This system, clearly distinct from the postsynaptosomal serotoninergic receptor, represents presumably a glial serotoninergic receptor; however, it cannot be totally excluded that these sites may refer to presynaptic membranes.

Adenylyl Cyclases↗
PubMed1980

[Connection between 3H 5-HT and adenyl cyclase activation induced by 5-HT in preparations of cerebral glial membranes].

Purified glial membrane preparations have been isolated from horse brain striatum. Tritiated 5-HT bound to these membranes with a high affinity (KD = 10 nM); the corresponding binding is reversible and appears specific of the serotoninergic structure. In parallel, 5-HT activates an adenylate cyclase with a low affinity (KD = 1 microM). The sites involved in this binding and in this adenylate cyclase activation appear different from the serotoninergic sites reported in the neuronal membrane preparations.

Adenylyl Cyclases↗