摘要:

By catalyzing the reaction of electrophilic compounds with the sulfhydryl group of glutathione, the glutathioneS‐transferases play physiologically important roles in the detoxication of potential alkylating agents. The glutathioneS‐conjugates thus formed are transported out of cells for further metabolism by γ‐glutamyltransferase and dipeptidases, ectoproteins that catalyze the sequential removal of the glutamyl and glycyl moieties, respectively. These ectoproteins are not found in all cells, but are localized predominantly to the apical surface of epithelial tissues. The resulting cysteineS‐conjugates can be reabsorbed by specific cell types, and acetylated on the amino group of the cysteinyl residue by intracellularN‐acetyl‐transferases, to form the corresponding mercapturic acids (N‐acetylcysteineS‐conjugates). Mercapturic acids are then released into the circulation and delivered to the kidney for excretion in urine, or they may undergo further metabolism. Mercapturic acid biosynthesis is generally considered to be an interorgan process, with the liver serving as the major site of glutathione conjugation, and the kidney as the primary site for conversion of glutathione conjugates to cysteine conjugates. Cysteine conjugates formed in the kidney appear to be transported back to the liver for acetylation. This interorgan model of mercapturic acid synthesis is based largely on the interorgan distribution of the enzymes involved in their formation, and in particular of the enzyme γ‐glutamyltransferase. Rats have relatively low hepatic and high renal activities of γ‐glutamyltransferase, the only protein known to initiate the breakdown of glutathioneS‐conjugates. The low γ‐glutamyltransferase activity in rat liver limits the hepatic degradation of glutathioneS‐conjugates, particularly after large doses of xenobiotic. In contrast, hepatic γ‐glutamyltransferase is significantly higher in species such as rabbit, guinea pig, and dog, and as a consequence, nearly all of the glutathione and glutathioneS‐conjugates released by liver cells of these species is degraded within the liver. Recent studies demonstrate that glutathioneS‐conjugates synthesized within hepatocytes are secreted preferentially across the canalicular membrane into bile, and are broken down within biliary spaces to form cysteineS‐conjugates. The latter are then reabsorbed by the liver,N‐acetylated to form mercapturic acids, and reexcreted into bile, completing an intra‐hepatic pathway for mercapturic acid biosynthesis. The contribution of this intrahepatic pathway to overall mercapturate formation is dependent on dose of the electrophile, route of exposure, and the physicochemical properties of the glutathioneS‐conjugate formed, as well as the tissue distribution and activity of γ‐glutamyltransferase. Intrahepatic mercapturic acid formation via the γ‐glutamyl cycle may provide an efficient mechanism of detoxification for a variety of electrophiles.

ISSN:0098-4108    

DOI:10.1080/15287399409531852

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

Fish contain methylamines, especially trimethylamine N‐oxide (TMAO), trimethylamine (TMA), and dimethylamine (DMA). Further, DMA may be formed from TMA and TMAO. DMA is a precursor of nitrosodimethylamine (NDMA), which is a potent carcinogen. Levels of DMA, TMA, and TMAO in urine were used as indicators of the dietary exposure and in vivo formation of these amines in 44 men, representing 3 groups with different fish consumption habits. The levels of TMA (median 0.24 mmol/mol creatinine; range 0–2.7) and TMAO (median 38 mmol/mol creatinine; range 8–290) were significantly associated with the weekly intake of fish (r = .47, p = .001, and r = .53, p = .0002, respectively), while no such relation was found for DMA (median 24 mmol/mol creatinine; range 5–46). Further, urinary levels of TMA and TMAO were dependent on recent intake of fish.

ISSN:0098-4108    

DOI:10.1080/15287399409531853

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

Percutaneous absorption of monosodium [14C]methanearsonate (MSMA) and disodium [14C]methanearsonate (DSMA) was investigated in female B6C3F1 mice from a variety of exposure vehicles, including aqueous solution, solid compound, and soil. These chemicals are the sodium sate of methanearsonic acid, an in vivo metabolite of inorganic arsenic compounds, and are present in water and soil. Permeation experiments were carried out in vitro for 24 h using previously clipped dorsal skin (area = 0.64 cm2) in flow‐through cells with HEPES‐buffered Hanks balanced salt solution as receptor fluid. Applied doses of 10 (15.6), 100 (156), and 500 (781) μg (μg/cm2) were studied in selected vehicles, and dermal absorption was quantitated by determining the radioactivity in the receptor fluid and skin following a skin surface wash to remove unpenetrated compound. Both MSMA and DSMA exhibited similar dermal absorption from different vehicles, and the rank order was aqueous solution > solid compound > soil. The degree of ionization of the compounds did not appear to affect their skin absorption, as both monobasic and dibasic forms penetrated mouse skin to the same extent from aqueous vehicles. An alteration in the aqueous donor volume (20, 100, and 250 μl) did not significantly change the total absorption of the chemicals; however, larger volumes significantly prolonged the time to reach maximal permeation rates. The major portion of the absorbed dose (53% or higher) remained in the skin for both chemicals. A constant fraction of the applied dose (12.4%) was absorbed from aqueous vehicles over the entire dosage range. Absorption of the chemicals was very low (<0.5% of the dose) from soil. Even short‐term (1 h) dermal exposure to an aqueous solution containing MSMA resulted in the penetration (0.66% of the dose) of this chemical. Thus, exposure vehicles have an important role in the in vitro dermal absorption of MSMA and DSMA in mouse skin, with aqueous solutions providing the greatest absorption.

ISSN:0098-4108    

DOI:10.1080/15287399409531854

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

The Canadian Wildlife Service monitors levels of polychlorinated aromatic hydrocarbons in great blue heron (Ardea herodias) eggs in British Columbia as indicators of environmental contamination. The present project assessed the temporal effects of environmental contamination with 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and other polychlorinated dibenzo‐p‐dioxins (PCDDs), dibenzofurans (PCDFs), and biphenyls (PCBs) on hepatic microsomal ethoxyresorufinO‐deethylase (EROD) activities and several morphological parameters in heron hatchlings. Between 1990 and 1992, eggs were collected from two great blue heron colonies in British Columbia that had elevated levels of contamination in 1988: Vancouver in 1990 and 1992, and Crofton in 1991. Biological parameters in the hatchlings and chemical contaminant levels in matched eggs from the same clutch were measured and compared with the findings from the same colonies studied in 1988. Levels of TCDD and other PCDDs and PCDFs had decreased significantly in both colonies since 1988. A concomitant decrease in EROD activity and incidence of chick edema, increase in body weight, and improvement of the reproductive success of the Crofton colony was observed. Body, yolk‐free body, stomach, and intestine weights, tibia wet, dry, and ash weights, and tibia length regressed negatively on TCDD level (p< .01;n= 54). Hepatic EROD activity regressed positively on TCDD level (r2= .49;p= .00005;n= 54). Regression of these parameters on the sum of TCDD toxic equivalents (TEQ) resulted in similar relationships. The reduction in severity of the effects observed in the contaminated colonies in the recent collections, accompanied by the declines in levels of PCDDs and PCDFs, was consistent with the dose‐response relationships determined in 1988.

ISSN:0098-4108    

DOI:10.1080/15287399409531855

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

Mixed halo‐ and haloalkyl‐substituted dibenzo‐p‐dioxins (DD) and dibenzofurans (DF) are known environmental contaminants, although there is limited information on the toxic effects of these compounds in human cells. In this study antiestrogenicity, a property of 2,3,7,8‐Cl4‐DD, was investigated with a series of bromochloro‐ and chloromethyl‐substi‐tuted DDs and DFs. The effects of these compounds on the metabolism of 17β‐estradiol (E2) and on the estrogen‐dependent formation of multicellular foci in cultures of MCF‐7 human breast cells were examined. Pretreatment of MCF‐7 cells with 2,3,7,8‐Cl4‐DD induced pathways of E2metabolism involving cytochrome P‐450‐catalyzed hydroxylation, methylation of the catechol estrogens, and conjugation. Several Br‐Cl3‐DD and Br2‐Cl2‐DD congeners with halogen substitution at the 2, 3, 7, and 8 positions also stimulated E2metabolism with similar potency to that of 2,3,7,8‐Cl4‐DD; however, compounds with substitution of a methyl group for a halogen at any of these positions did not stimulate the metabolism of E2. For the series of compounds tested in MCF‐7 cultures, a close correlation was observed between the antiestrogenicity as measured by the inhibition of estrogen‐dependent postconfluent growth that results in focus formation and the efficacy with which the compounds stimulated the metabolism of E2. 2,3,7,8‐TetrahaloDDs with one or two bromine atoms at these positions were highly antiestrogenic as determined by their inhibition of estrogen‐dependent focus formation, whereas the methyl‐substituted polychlorinated DDs and DFs investigated did not inhibit focus formation. These results indicate that the 2,3,7,8‐substituted mixed halo‐substituted DDs and DFs are of importance when the biologic effects of halogenated DD and DF congeners are considered, and provide additional evidence for the role of increased metabolism of E2in the antiestrogenic effects of halogenated DDs and DFs.

ISSN:0098-4108    

DOI:10.1080/15287399409531856

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

Skin is a primary route of exposure to phenol, a major chemical found in hazardous waste sites. The effect of soil adsorption on the dermal bioavailability of phenol was assessed by applying [14C]phenol alone (P) or with sandy (PS) or clay (P‐C) soil to dermatomed male pig skin samples in flow‐through diffusion cells. Maximum penetration of P‐S and P‐C was significantly decreased by one‐half and by two‐thirds, respectively, compared to P. Furthermore, the penetration of phenol into receptor fluid and the amount bound to skin were significantly lower when phenol was adsorbed to either soil versus P. While less radioactivity penetrated skin with soil‐adsorbed phenol treatment than P, significantly more radioactivity was loosely adsorbed to skin and could be easily washed off of the skin surface by soap and water. Only a small fraction (<5%) of the chemical was metabolized by skin to hydroquinone and cate‐chol in all treatment groups. The results of this study indicate that the bioavailability and thus the potential health risk from dermal exposure to phenol is reduced if the chemical is adsorbed to soil.

ISSN:0098-4108    

DOI:10.1080/15287399409531857

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

The half‐life of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) changed significantly with body fat and age in 337 members of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of Agent Orange in Vietnam. Using paired TCDD measurements derived from serum collected in 1982 and in 1987, we investigated how TCDD half‐life varied with percent body fat (PBF), relative changes in PBF, and age. We found that half‐life increased significantly with increasing PBF and decreased significantly with increasing relative change in PBF and with age. The median observed half‐life of TCDD for these 337 veterans is 11.3 yr with a nonparametric 95% confidence interval of 10.0–14.1 yr.

ISSN:0098-4108    

DOI:10.1080/15287399409531858

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

Free radical‐induced oxidative stress has been linked to ischemia‐reperfusion injury of the myocardium. The ‘OH radical is considered the most damaging radical and can be increased in cells by treatment in vitro with H2O2. The purpose of the present study was to determine if aliphatic halocarbons enhance H2O2‐induced oxidative injury in isolated cardiac myocytes from neonatal rats. Oxidative damage was assessed by measuring release of thiobarbituric acid‐reactive substances (TBARS) from lipid peroxidation, loss of lactate dehydrogenase (LDH) through damaged sarcolemmal membranes, and alterations in intra‐cellular calcium ([Ca2+]i) transients in electrically stimulated (1 Hz, 10 ms, 60 V) myocytes. H2O2increased TBARS release and LDH leakage in a concentration‐dependent (20–200 μM) manner. Continuous suffusion with H2O2first altered the configuration of [Ca2+]itransients, then eliminated them, and finally caused [Ca2+]ioverload (basal [Ca2+]iexceeded peak systolic [Ca2+]iof control). The time to [Ca2+]ioverload was inversely associated with concentration, and the shortest time to overload was obtained with 100 μM H2O2. A 1‐h preincubation of myocytes with the iron chelator deferoxamine inhibited all effects of H2O2. 1,1,1‐Trichloroethane, carbon tetrachloride, or hatothane at 1 mM significantly and reversibly reduced [Ca2+]itransients but did not influence TBARS release or LDH leakage. Simultaneous exposure of myocytes to H2O2and halocarbons did not affect the myocyte response to H2O2exposure. Results indicate that the three halocarbons tested do not enhance H2O3‐induced oxidative injury in isolated cardiac myocytes.

ISSN:0098-4108    

DOI:10.1080/15287399409531859

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287399409531851

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor