N2-ethylidene-2'-deoxyguanosine (N2-ethylidene-dG) is a major DNA adduct induced by acetaldehyde. Although it is unstable in the nucleoside form, it is relatively stable when present in DNA. In this study, we analyzed three acetaldehyde-derived DNA adducts, N2-ethylidene-dG, N2-ethyl-2'-deoxyguanosine (N2-Et-dG) and alpha-methyl-gamma-hydroxy-1,N2-propano-2'-deoxyguanosine (alpha-Me-gamma-OH-PdG) in the liver DNA of aldehyde dehydrogenase (Aldh)-2-knockout mice to determine the influence of alcohol consumption and the Aldh2 genotype on the levels of DNA damage. In control Aldh2+/+ mice, the level of N2-ethylidene-dG adduct in liver DNA was 1.9 +/- 0.7 adducts per 10(7) bases and was not significantly different than that of Aldh2+/- and -/- mice. In alcohol-fed mice (20% ethanol for 5 weeks), the adduct levels of Aldh2+/+, +/- and -/- mice were 7.9 +/- 1.8, 23.3 +/- 4.0 and 79.9 +/- 14.2 adducts per 10(7) bases, respectively, and indicated that adduct level was alcohol and Aldh2 genotype dependent. In contrast, an alcohol- or Aldh2 genotype-dependent increase was not observed for alpha-Me-gamma-OH-PdG, and N2-Et-dG was not detected in any of the analyzed samples. In conclusion, the risk of formation of N2-ethylidene-dG in model animal liver in vivo is significantly higher in the Aldh2-deficient population and these results may contribute to our understanding of in vivo adduct formation in humans.
. Urinary excretion of hippuric acid and m-or p-methylhippuric acid in the urine of persons exposed to vapours of toluene and m-or p-xylene as a test of exposure. Twenty-three male volunteers were exposed in groups of four or five to toluene and m-and p-xylene vapour for periods of 3 hours or of 7 hours with one break of an hour. Urine was collected at hourly intervals for several hours, and thereafter all urine was collected until 18 hours after the end of the exposure period, and was analysed for hippuric and methylhippuric acids. It was shown that hippuric acid was excreted equivalent to 68 % of the toluene absorbed, and m-methylhippuric acid equivalent to 72% of the m-xylene absorbed. Up to hydrocarbon concentrations of 200 ppm the total quantity of hippuric acids excreted was proportional to the total exposure (ppm x hours). In descending order of precision the following were also related to exposure: rate of excretion during the exposure period; concentrations of hippuric acid in urine corrected to constant urine density; and concentrations in urine uncorrected for density. The last could not be used to calculate exposure, but the others could be to give screening tests to show whether workmen could have been exposed to concentrations greater than the maximum allowable.The effects of exposure on blood pressure, pulse rate, flicker value, and reaction time were measured. There were some variations which suggested that the MAC of toluene should be set higher than 200 ppm.For the reasons given by Ogata, Tomokuni, and Takatsuka (1969), exposure to toluene and m-or p-xylene is best estimated by determining the quantities of their metabolites, hippuric acid and m-or p-methylhippuric acid, excreted in the urine. Using the analytical methods already described (Ogata et al., 1969) we show here how the quantities of metabolites are related to exposure, and consequently what levels of metabolites in urine cor-
Intrathecal administration of baclofen, a GABA(B)-receptor agonist, affects pain behavior induced by formalin in a biphasic manner; baclofen at low doses enhances pain while producing antinociception at high doses. This may be due to the fact that baclofen modulates each of excitatory and inhibitory transmission in the dorsal horn of the spinal cord with a distinct sensitivity, resulting in a biphasic action on pain transmission. To address this issue, we examined the actions of baclofen on miniature excitatory (glutamatergic) and inhibitory (GABAergic) postsynaptic currents (mEPSCs and mIPSCs, respectively) in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using the whole-cell voltage-clamp technique. Baclofen reduced the frequency of both mEPSC and mIPSC without a change in their amplitudes. These actions were dose-dependent in a concentration range of 0.1-100 microM; the effective concentrations for the half-inhibition of mEPSC and mIPSC frequency were 4.44+/-0. 60 microM (n=7) and 4.31+/-0.77 microM (n=6), respectively. These results indicate that each of glutamatergic and GABAergic nerve terminals in the SG is endowed with the GABA(B) receptor, the activation of which depresses the release of neurotransmitter from the terminal; this provides a cellular basis for the modulation of pain by baclofen. It is suggested from a similar affinity for baclofen of the GABA(B) receptors on both terminals that the baclofen-induced biphasic action on pain behaviors cannot be accounted for by only its presynaptic actions in the SG and that other actions such as an inhibitory action of baclofen on postsynaptic neurons also have to be taken into consideration.
A fluorometric high-performance liquid chromatographic (HPLC) method was developed for the highly sensitive measurement of delta-aminolevulinic acid (ALA) in biological materials. By using this method, we determined ALA in the plasma and urine of 418 workers occupationally exposed to lead and in the plasma and urine of 227 controls. The concentrations of ALA in the plasma and urine of lead workers were significantly elevated as compared with those of the controls. The concentration of ALA in plasma and urine was highly correlated with that of lead in blood in lead workers. It was found that the correlation (r = 0.742) between log of plasma ALA concentrations and blood lead concentrations in lead workers was similar to that (r = 0.711) between log of urine ALA concentrations and blood lead concentrations. These results demonstrated that the measurement of ALA in plasma or in urine using a fluorometric HPLC method was useful for the biological monitoring of lead workers.
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