SYNOPSISL-tryptophan 50 mg/kg was administered orally to patients suffering from either unipolar or bipolar affective illness, and the concentration of 5-hydroxyindol-acetic acid estimated in their cerebrospinal fluid eight hours later. There was no significant difference between the patient groups or between these and patients with neurological disease. These findings suggest a reduced neuronal activity in the 5-hydroxytryptaminergic system in some depressed patients rather than an absolute deficiency of tryptophan-5-hydroxylase. The synthesis of 5-HIAA in response to tryptophan varied with age.
HESS, REDFIELD and UDENFRIEND (1959) reported the presence of tryptamine in brain under certain circumstances. They did not detect it in the brains of normal animals (rat, guinea pig and dog), but found the amine in the brains of guinea pigs treated with L-tryptophan, or with a combination of L-tryptophan and the amine oxidase inhibitor, iproniazid. The method, solvent-extraction followed by fluorescence assay, was used subsequently by other workers ( GREEN and SAWYER, 1960;HESS and DOEPFNER, 1961) to determine the tryptamine content of brain under various experimental conditions. During a study of the effect of tryptophan administration in rats on the concentration of 5-hydroxyindole compounds in whole brain, ASHCROFT, ECCLESTON and CRAWFORD (1965), using a method involving separation by paper chromatography, attempted to examine in parallel the levels of tryptamine in the brain. Using this technique, they were unable to detect tryptamine in the brains of untreated animals, while in animals to which tryptophan had been given only very small amounts of the amine were detected. The present paper presents an investigation of the discrepancy between these results and those previously reported, together with a critical reevaluation of the solvent-extraction technique of HESS and UDENFRIEND (1959). A description of a modification of the method of HESS and UDENFRIEND (1959), incorporating ion-exchange chromatography, is presented. METHODSAnimal treatment. The animals were killed by decapitation and the blood collected from the neck wound into a polythene tube containing heparin (0.2 ml; 100 I.U./ml). The contents of the tube were mixed by gentle shaking.Iproniazid phosphate (60 mg/ml in saline) was administered by intraperitoneal injection to 200 g guinea pigs in groups of three, in a dose of 150 mg/kg. Sixteen hours later, L-tryptophan (800 mg/kg) was given by the intraperitoneal route to the animals in a 2 ml saline suspension, prepared as described by HESS et al. (1959). The animals were killed in groups of three at 20, 40, 60, 80 and 120 min following the administration of tryptophan. Further groups of guinea pigs were given L-tryptophan by the same route, without pre-treatment with iproniazid, and killed at comparable times following the administration of the amino acid. A group of untreated animals and a group treated 16 hr previously with iproniazid, but without injection of tryptophan, were examined as controls. Preparation of tissue andplasma extracts. Plasma: The blood was centrifuged at 2500 revslmin for 10 min and the plasma separated off. A 2 ml portion of the plasma was diluted to 10 ml with deionized distilled water. Zinc sulphate solution (2m1, 10% w/v) was added with mixing. The proteins were precipitated by the addition of 0.2 ml20% (w/v) NaOH, when the tube was immediately inverted gently 3 times to ensure adequate mixing. After standing for 10 min, the tube was centrifuged for 5 min at 2500 revslmin and the supernatant fluid transferred to a 10 ml beaker. After adjustment of the pH to 7.5 (glass ele...
The in vivo genotoxic activities in mouse skin of the dimethyl sulphoxide (DMSO) extracts of a range of oil products [residual aromatic extract; untreated heavy paraffinic distillate aromatic extract; mildly refined light naphthenic base oil; bitumen (vacuum residue); high viscosity index base oil obtained by catalytic hydrogenation] were evaluated by 32P-postlabelling DNA analysis. The results of quantitative 32P-postlabelling analyses of epidermal DNA from mice treated with the DMSO extracts showed linear relationships with the total polycyclic aromatic compound (PAC) contents, determined by the Institute of Petroleum method IP 346 and also the 3-6 ring PAC contents, measured by on-line liquid-liquid extraction using flow injection analysis. The 32P-postlabelling data also showed a linear relationship with the mutagenicity indices of these oil products determined in S. typhimurium TA98 using the modified Ames Salmonella microsome test. The in vivo genotoxicity of the DMSO extracts from the oil products was low, judged by 32P-postlabelling analysis of DNA adducts measured in epidermal DNA of treated mouse skin, and ranging from 2 to 723 attomole/microg DNA per mg oil product. The in vivo 32P-postlabelling data from this study are consistent with these materials expressing low genotoxicity in mouse skin in vivo. The DMSO extraction procedure coupled with 32P-postlabelling DNA analysis is useful for ranking the relative genotoxic potency in vivo of a wide range of oil products. In general the trend observed is similar to rankings based on physicochemical measurements of total PAC contents or 3 6 ring PAC contents of the oil products.
The assessment of skin penetration by viscous oil products is an important element in the risk assessment of these materials where skin contact is likely. Systemic bioavailability (body uptake) is viewed as a good indicator of skin penetration following cutaneous exposures. The results of this study provide quantitative information on the influence of viscosity on the bioavailability of a specific polycyclic aromatic compound (benzo(a)pyrene) in base oils, residual aromatic extracts and bitumens following skin exposures to mice. The materials studied were a base mineral oil (viscosity 32 cSt at 35 degrees C), a 1:1 blend of the mineral base oil and a residual aromatic extract (198 cSt), several residual aromatic extracts (ca. 5000 cSt, 35 degrees C) and a range of bitumens (0.65-69 x 10(6) cSt, 35 degrees C). These were each spiked with 0.1% radiolabelled benzo(a)pyrene, as a representative carcinogenic polycyclic aromatic compound, then used for cutaneous exposures to mice. The results indicate that as viscosity increased in the range ca. 30 to 5000 cSt (base oil to residual aromatic extract) the uptake of the radiolabelled benzo(a)pyrene into blood was reduced by ca. fivefold. Further increases in viscosity from ca. 5000 to 69 x 10(6) cSt (i.e. residual aromatic extract to bitumen) resulted in a further but smaller (ca. twofold) reduction in uptake. The relationship between the amounts of free benzo(a)pyrene measured in blood and viscosity showed the same trend. This trend was also mirrored by the degree of binding of benzo(a)pyrene metabolites to DNA in skin. The findings in mouse skin in vivo indicate that viscosity can significantly affect skin penetration and systemic bioavailability of polycyclic aromatic compound components of oil products. Results obtained with viable human skin in vitro also showed that the bioavailability of benzo(a)pyrene was reduced by the viscosity of the oil product matrix. It is thus necessary to take account of physical properties such as viscosity in the overall risk assessment of viscous oil products, particularly in the case of very viscous materials such as bitumens. The significantly reduced bioavailability of hazardous compounds from undiluted materials is thus an important factor to consider when assessing the risks from dermal exposures.
The effect of solvent polarity and lipophilicity on DNA adduct formation by polycyclic aromatic hydrocarbons in skin and lung has been studied in CD1 mice exposed cutaneously in vivo to benzo(a)pyrene ( approximately 0.01-7.0 microg/animal) in either tetrahydrofuran or n-dodecane. The nature and amounts of DNA adducts, measured as 7R,8S, 9R-trihydroxy-10S-(N(2)-deoxyguanosyl-3'-phosphate)-7,8,9, 10-tetrahydrobenzo(a)pyrene, in relation to exposure dose and treatment regime was determined by (32)P-postlabelling. In skin DNA there was a linear relationship between exposure dose and adduct formation with both solvents, though the amount of adduct formed was significantly lower from treatment with benzo(a)pyrene in n-dodecane than in tetrahydrofuran. The amounts of adducts measured in skin DNA ranged from 67 amol adducts/microg DNA at the lowest exposure dose of benzo(a)pyrene in n-dodecane to 3.5 fmol adducts/microg DNA (1 adduct in 5 x 10(7) nucleotides to 1 adduct in 9 x 10(5) nucleotides) at the highest dose. In tetrahydrofuran the corresponding levels were 89 amol adducts/microg DNA (1 adduct in 3 x 10(7) nucleotides) to 16.9 fmol adducts/microg DNA (1 adduct in 2 x 10(5) nucleotides). DNA adducts could not be detected in lung tissue following cutaneous treatment of animals with benzo(a)pyrene in n-dodecane. Cutaneous treatment of animals with benzo(a)pyrene in tetrahydrofuran, however, resulted in adducts in lung DNA at a level of 88 amol/microg DNA from exposures only at the highest dose (6.72 microg/animal). The difference in octanol-water partition coefficient, log P(ow) between n-dodecane compared to tetrahydrofuran is considered to be the most likely reason for the reduction in the bioavailability of benzo(a)pyrene and/or its metabolites and hence the degree of genotoxicity in tissues. The results suggest that other paraffinic hydrocarbon solvents may moderate the genotoxicity of polycyclic aromatic hydrocarbons in vivo. The assessment of the genotoxicity in vivo of mixtures of compounds should be carried out on complete mixtures of substances of interest in order to take account of these possible antagonistic or synergistic effects.
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