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1. |
Pharmacokinetics of propetamphos following intravenous administration in the F344 rat |
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Journal of Biochemical Toxicology,
Volume 7,
Issue 4,
1992,
Page 199-204
Kelly Dix,
Leo T. Burka,
Walter C. Dauterman,
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摘要:
AbstractPropetamphos [(E)‐l‐methylethyl 3[[(ethylamino)methoxyphosphinothioyl]oxy]‐2‐bu‐tenoate], the active ingredient in Safrotin,® is an organophosphate developed by Sandoz, Ltd.® (Switzerland) as an insecticide (1). Although metabolism of propetamphos has been previously investigated (2,3), there is no pharmacokinetic data available in the literature. The current studies were undertaken to investigate the pharmacokinetics of propetamphos following intravenous administration in male and female Fischer 344 (F344) rats. Rats were dosed via an indwelling jugular cannula at a dose of 12 mg/kg (one‐tenth the oral LD‐50). Blood samples were withdrawn via the cannula at predetermined timepoints to quantitate plasma concentrations of propetamphos over time. Propetamphos is highly bound to plasma proteins (free fraction = 0.06). Free propetamphos concentration in plasma vs. time data were analyzed by noncompartmental methods. The terminal elimination rate constant, λ, was significantly different for males versus females (0.015 min−1for males and 0.037 min−1for females,p= 0.001). Plasma was cleared of unbound propetamphos at rates of 0.559 ± 0.069 and 0.828 ± 0.181 L/min/kg for males and females (mean ± standard error). Mean residence times (MRTs) for propetamphos in the body for males and females were 28.3 ± 5.7 and 14.4 ± 3.5 min, and the volume of distribution at steady state (Vss) was 14.7 ± 2.6 and 12.3 ± 4.5 L/kg. The differences in these parameters, clearance (CI), MRT, andVss, were not statistically significant at thep<0.05 level for males versus females, but MRT was nearly significantly different (p= 0.08). Because of the rapid elimination of propetamphos from plasma following intravenous administration, it is unlikely that propetamphos would bioaccumulate in environmentally exposed animals. Although the pharmacokinetic parameters were not statistically different for males and females in these studies, there was a clear clinical difference in their susceptibility to propetamphos toxicity. Female rats presented with overt signs of organophosphate intoxication, whereas males were only slightly effected. The observed gender‐related clinical difference in susceptibility to toxicity suggests that there may be a difference in the extent of elimination due to activation versus detoxication of propetamphos in males and females. Another possible explanation for the clinical difference in propetamphos toxicity is that inhibition of acetyl‐cholinesterase by the activated, oxygenated form of propetamphos (propetamphos oxon) may be g
ISSN:0887-2082
DOI:10.1002/jbt.2570070402
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1992
数据来源: WILEY
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2. |
Perfluorooctanoic acid has persistent effects on peroxisome proliferation and related parameters in mouse liver |
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Journal of Biochemical Toxicology,
Volume 7,
Issue 4,
1992,
Page 205-212
Anna‐Karin Sohlenius,
Bo Lundgren,
Joseph W. DePierre,
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摘要:
AbstractMale C57B1/6 mice were treated for 5 days with 0.05% perfluorooctanoic acid (PFOA) in their diet. This treatment resulted in a potent induction of peroxisomal fatty acid β‐oxidation in the liver. In order to investigate recovery from treatment with PFOA, mice were given normal laboratory chow for up to 20 days after termination of PFOA administration. It was established that the activities of peroxisomal lauoryl‐CoA oxidase and palmitoyl‐CoA oxidation were still elevated 2–3 weeks after termination of treatment. The catalase activity recovered in the cytosolic fraction was also still significantly elevated after 20 days with normal laboratory chow. Furthermore, the protein content of the mitochondrial fraction was increased by PFOA and had not returned to control level at the end of the recovery period. Perfluorooctanoic acid also caused a persistent effect in omega hydroxylation of lauric acid (cytochrome P‐452). The activities of cytosolic DT‐diaphoreses and glutathione transferase were also enhanced by PFOA. However, these two enzymes recovered relatively rapidly from the treatment (2–20 days). This study reveals two different patterns of recovery from PFOA treatment, one involving parameters that recovered completely, or almost completely, from PFOA treatment after 20 days and another involving parameters that were still elevated at the end of the r
ISSN:0887-2082
DOI:10.1002/jbt.2570070403
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1992
数据来源: WILEY
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3. |
Strand scission in DNA by Gossypol and Cu(II): Role of Cu(I) and oxygen‐free radicals |
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Journal of Biochemical Toxicology,
Volume 7,
Issue 4,
1992,
Page 213-217
Rana Zaidi,
S. M. Hadi,
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摘要:
AbstractGossypol, a polyphenolic binaphthyl dialdehyde found in cotton seeds, is a dietary mutagen and a potential male contraceptive. In the presence of Cu(II), gossypol caused breakage of supercoiled plasmid pBR322 DNA. The products were relaxed circles or a mixture of these and linear molecules. Other metal ions tested [Ni(II), Co(II), Mn(II), and Fe(II)] were ineffective or less effective in the DNA breakage reaction. In the case of gossypol‐Cu(II) mediated cleavage, (Cu(I) was shown to be an essential intermediate by using the Cud) sequestering reagent bathocuproine. By using job plots, it was established that in the absence of DNA, eight Cu(II) ions can be reduced by one gossypol molecule. The involvement of active oxygen species, such as singlet oxygen and H2O2, was established by the inhibition of DNA breakage by catalase and by sodium azide. It was further shown that gossypol is capable of directly producing H2O
ISSN:0887-2082
DOI:10.1002/jbt.2570070404
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1992
数据来源: WILEY
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4. |
Heterogeneity of antibodies to metallothionein isomers and development of a simple enzyme‐linked immunosorbent assay |
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Journal of Biochemical Toxicology,
Volume 7,
Issue 4,
1992,
Page 219-227
Hing Man Chan,
Gordon A. Pringle,
M. George Cherian,
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摘要:
AbstractA competitive enzyme‐linked immunosorbent assay (ELISA) for the measurement of metallothionein (MT) in tissues and body fluids has been developed. The ELISA employs the IgG fraction of a rabbit antiserum to rat liver Cd‐MT‐2 polymer, a biotinylated secondary antibody, and peroxidase conjugated avidin. With a 1:4000 dilution of the immunoglobulins, typical standard curves (logit‐log regression) provide a linear range of 0.1–100 ng for MT‐2 and 10–1000 ng for MT‐1. Fifty percent inhibition is accomplished with 15 ng and 250 ng for MT‐2 and MT‐1, respectively. Rat liver MT‐1 and MT‐2 containing different metals (Ag, Cu, and Zn) inhibited the antibodies as effectively as CdMT. However, the antibodies exhibited greater affinity for both Apo‐MT isoforms. Previously reported discrepancies between results obtained by metal binding assays (e.g., Ag‐hem binding) and radioimmunoassay for MT levels in tissues have been largely resolved. By addition of 1% Tween 20 to samples, the ELISA routinely estimated the total MT in samples of rat, mouse, and human liver and kidney at 88% of the value obtained by the silver‐hem binding assay. Specific antibodies to MT‐2 were purified from our anti‐serum by affinity purification using CH‐Sepharose 4B coupled with rat liver MT‐1. Estimation of MT in samples using purified MT‐2 antibodies provided slightly lower values (72%) for MT in tissues as compared to the Ag‐hem method. The predominant form of MT in tissues of control animals was found to be MT‐2. Therefore, the MT‐2 specific antibodies may be useful for the study of the functions of MT isoforms. Levels of total MT in tissues and biological fluids of rats injected with CdCl2(0.3 mg Cd/kg) and Cd‐MT (0.3 mg Cd/kg) were estimated by ELISA. The results suggest ur
ISSN:0887-2082
DOI:10.1002/jbt.2570070405
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1992
数据来源: WILEY
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5. |
Effects of niacin on bleomycin‐induced increases in myeloperoxidase, prolyl hydroxylase, and superoxide dismutase activities and collagen accumulation in the lungs of hamsters |
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Journal of Biochemical Toxicology,
Volume 7,
Issue 4,
1992,
Page 229-239
Charles A. O'Neill,
Shri N. Giri,
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摘要:
AbstractIt has been shown that lung nicotinamide adenine dinucleotide (NAD) depletion accompanies bleomycin (BL)‐induced lung fibrosis in the hamster and that treatment with niacin (NA), a precursor of NAD, was found to attenuate lung fibrosis caused by this agent. Niacin was used in the present study to investigate changes in some biochemical parameters and enzymes involved in the development of BL‐induced lung fibrosis in the hamster. Niacin (500 mg/kg, IP), or an equivalent volume of saline (SA, IP), was given daily 2 days prior to intratracheal instillation of BL (7.5 U/5 mL/ kg) or SA and everyday thereafter throughout the study. Hamsters were killed at 1, 4, 7, 10, and 14 days after the BL or SA instillation and their lungs processed for various biochemical assays. Hydroxyproline content and superoxide dismutase (SOD) activity in SABL treated animals were significantly (P± 0.05) elevated at 7 and 10 days, peaking at 14 days to 161 ± 11% and 159 ± 11% of the SASA treated animals, respectively. Although the hydroxyproline level of NABL treated animals was significantly elevated at 7 and 10 days and peaked at 14 days to 123 ± 8% of the NASA control, these values were significantly lower than the SABL treated animals at the corresponding times. The lung SOD activity of NABL groups was significantly higher at 4 days but significantly lower at 10 and 14 days than the SABL groups at the corresponding times. Prolyl hydroxylase (PH) activity and total lung calcium in SABL treated groups were significantly elevated compared to SASA treated groups starting at 4 days, with PH peaking at 10 days to 163 ± 13% and calcium peaking at 7 days to 148 ± 8% of SASA treated groups. The NABL treated animals displayed a significant elevation in PH activity at 4 days only (132 ± 15%), while the calcium content in this group was significantly increased at 4 and 14 days compared to NASA treated animals. However, the activity of PH in the NABL treated animals was significantly lower than the SABL treated animals at 7, 10, and 14 days. The calcium content of the NABL group was significantly lower than the SABL group at 7 and 10 days. The thiobarbituric acid reactive substance equivalents (TBARS) content and myeloperoxidase (MPO) activity were significantly elevated at all time points in SABL groups as compared to SASA groups, with peak elevation of TBARS to 160 ± 9% at 4 days and MPO to 268 ± 40% at 1 day. The TBARS content of NABL groups was significantly elevated above NASA groups at 1, 4, 7, and 10 days. The MPO activity in NABL groups was significantly elevated above NASA groups at 1, 4, 7, and 14 days, but the activity was significantly lower than SABL groups at 4 and 14 days. The data suggest that NA inhibits the extent of oxidative damage or enhances processes involved in the repair of BL‐induced alveolar epi
ISSN:0887-2082
DOI:10.1002/jbt.2570070406
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1992
数据来源: WILEY
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6. |
Bioactivation of 7‐hydroxymethyl‐12‐ methyibenz[a]anthracene by rat liver bile acid sulfotransferase I |
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Journal of Biochemical Toxicology,
Volume 7,
Issue 4,
1992,
Page 241-248
Charles N. Falany,
James Wheeler,
Lori Coward,
Dawn Keehan,
Josie L. Falany,
Stephen Barnes,
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摘要:
AbstractThe bioactivation of 7‐hydroxy‐methyl‐12‐methylbenz[a]anthracene (HMBA) to an electrophilic sulfuric acid ester metabolite has been shown to be catalyzed by rat liver bile acid sulfotransferase I (BAST I). The sulfation and activation of HMBA by BAST I was determined by the ability of sulfated HMBA to form DNA ad‐ducts. The BAST I was also shown to react with rabbit anti‐human dehydroepiandrosterone sulfotransferase antisera and to represent a major form of hydroxysteroid/bile acid sulfotransferase in female rat liver cytosol. Higher levels of BAST I activity and immunoreactivity as well as HMBA‐DNA adduct formation were detected in female rat liver cytosol than in male rat liver cytosol. The bioactivation of HMBA by pure BAST I was dependent on the presence of 3′‐phosphoadenosine 5′‐phos‐phosulfate (PAPS) in the reaction and was inhibited by dehydroepiandrosterone, a physiological substrate for BAST I. Glutathione, a cellular nucleophile with important protective properties, decreased DNA adduct formation in the HMBA sulfation reaction in the absence of glutathione S‐transferase activity. These results indicate the usefulness of BAST I to investigate the sulfation and activation of HMBA and probably other hydroxy‐methylated polyaromatic hydrocarbons to electrophilic and mutagenic metabolites under
ISSN:0887-2082
DOI:10.1002/jbt.2570070407
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1992
数据来源: WILEY
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7. |
Heterogeneity of rat hepatic Ah Receptor: Identification of two receptor forms which differ in their biochemical properties |
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Journal of Biochemical Toxicology,
Volume 7,
Issue 4,
1992,
Page 249-256
Michael S. Denison,
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摘要:
AbstractIn cytosol, the rat hepatic Ah receptor (AhR) appears to exist in two distinct forms (AhRα, AhRβ) in similar concentration. The binding of ligand (2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD)) to AhRαrequires the receptor be in its oligomeric 8–10 to S conformation (bound to other protein subunits), while ligand binding to AhRβcan occur with the dissociated 5–6 S form. Occupancy of AhRβby ligand (TCDD) protects it from salt‐dependent inactivation; AhRβis not inactivated by high salt conditions. The addition of molybdate to cytosol during tissue homogenization stabilized AhRαagainst salt‐dependent inactivation and subunit dissociation but did not prevent dissociation of AhRβby high salt. Although the presence of molybdate appears to stabilize AhRαin its oligomeric 8–10 S, it had no significant effect on the overall amount of TCDD:AhR complex which bound to its specific DNA recognition site, the dioxin responsive element (DRE). These results suggest that AhRα, unlike AhRβ, is either unable to transform or bind to
ISSN:0887-2082
DOI:10.1002/jbt.2570070408
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1992
数据来源: WILEY
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8. |
The differential hepatotoxicity and cytochrome P450 responses of fischer‐344 rats to the three isomers of dichlorobenzene |
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Journal of Biochemical Toxicology,
Volume 7,
Issue 4,
1992,
Page 257-264
John W. Allis,
Jane Ellen Simmons,
Dennis E. House,
Barbara L. Robinson,
Ezra Berman,
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摘要:
AbstractThe acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene (DCB) have been investigated. The objectives were to estimate the onset of toxicity and to further elucidate the role of cytochrome P450 in the metabolism and toxicity of these compounds. In a study design employing one animal per dose level, Fischer‐344 rats were gavaged with up to 25 different dosages, then evaluated 24 h later. Hepatic necrosis, serum alanine aminotransferase, and serum aspartate aminotransferase exhibited similar patterns demonstrating thatortho‐DCB (O‐DCB) was the most toxic in terms of both earliest onset and degree of response at higher dosages. For these three end‐points,meta‐DCB (m‐DCB) exhibited a lesser toxicity.Para‐DCB (p‐DCB) did not cause changes in these three endpoints, but hepatic degenerative changes were found. Total hepatic cytochrome P450 responses were also different after treatment with each isomer. Theo‐DCB produced a dose‐dependent decrease in P450 beginning at dosages lower than the onset of necrosis and appeared to be a suicide substrate for P450. Them‐DCB treatment increased P450 at dosages below the onset of necrosis and decreased P450 at higher dosages, with the decline preceding the onset of hepatocyte death. Treatment withp‐DCB increased P450 beginning at 380 mg/kg. The combination of toxicity and P450 profiles has provided a framework for interpreting literature data on the metabolism and toxicity of the DCBs in rats. It is also noteworthy thato‐DCB andp‐DCB were administered at dosages several times the oral rat LD‐50
ISSN:0887-2082
DOI:10.1002/jbt.2570070409
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1992
数据来源: WILEY
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9. |
Masthead |
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Journal of Biochemical Toxicology,
Volume 7,
Issue 4,
1992,
Page -
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ISSN:0887-2082
DOI:10.1002/jbt.2570070401
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1992
数据来源: WILEY
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