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Archives of Toxicology (v.72, #3)
Structure-activity relationships of volatile organic chemicals as sensory irritants by Y. Alarie; M. Schaper; G. D. Nielsen; M. H. Abraham (pp. 125-140).
We used a database of 145 volatile organic chemicals for which the sensory irritation potency (RD50) has been reported in mice. Chemicals were first separated into two groups: nonreactive and reactive, using Ferguson's rule. This rule suggests that nonreactive chemicals induce their effect via a physical ( p) mechanism (i.e., weak forces or interactions between a chemical and a biological receptor). Therefore, appropriate physicochemical descriptors can be used to estimate their potency. For reactives, a chemical (c) mechanism (i.e., covalent bonding with the receptor) would explain their potency. All chemicals were also separated on the basis of functional groups and subgroups into 24 classifications. Our results indicated that the potency of nonreactive chemicals, regardless of their chemical structure, can be estimated using a variety of physicochemical descriptors. For reactive chemicals, we identified five basic reactivity mechanisms which explained why their potency was higher than that estimated from physicochemical descriptors. We concluded that Ferguson's proposed rule is adequate initially to classify two separate mechanisms of receptor interactions, p vs c. Several physicochemical descriptors can be used to estimate the potency of p chemicals, but chemical reactivity descriptors are needed to estimate the potency for c chemicals. At present, this is the largest database for nonreactive-reactive chemicals in toxicology. Because of the wide variety of c chemicals presented, a semi-quantitative estimate of the potency of new, or not previously evaluated, c chemicals can be arrived at via comparison with those presented and the basic chemical reactivity mechanisms presented.
Keywords: Key words Sensory irritation; Structure activity relationship; Quantitative structure-activity relationships; QSAR
Airway hyperreactivity elicited by toluene diisocyanate (TDI)-albumin conjugate is not accompanied by airway eosinophilic infiltration in guinea pigs by Jun Huang; Lyndell L. Millecchia; David G. Frazer; Jeffrey S. Fedan (pp. 141-146).
Nonspecific airway hyperresponsiveness is present in many patients with toluene diisocyanate (TDI)-induced asthma; however, the underlying pathophysiological mechanisms of this hyperresponsiveness remain controversial. In the present study, we used a guinea pig model to investigate the association of TDI-induced airway hyperresponsiveness with eosinophilic airway infiltration, which is widely considered to play a key role in the development of allergen-induced hyperresponsiveness. Guinea pigs were sensitized by i.d. injections of 10 μl TDI on day 1 and day 6. Control animals received saline injections. Two weeks after the second injection, airway reactivity to inhaled methacholine and specific airway resistance (sRaw) was measured before and at several times after inhalation challenge with TDI-GSA (guinea pig serum albumin) conjugates. Eosinophils in the airways were detected using enzyme histochemistry and quantified using computer-assisted image analysis. TDI-specific IgG1 antibodies were found in the blood of TDI-sensitized animals. An immediate increase in sRaw was induced in these animals by TDI-GSA challenge; airway hyperresponsiveness to methacholine was observed at 6 h and 18 h after TDI-GSA challenge. However, TDI-GSA challenge did not result in an elevation of eosinophils in the airways, compared with control animals. The results suggest that the development of TDI-induced airway hyperresponsiveness is not dependent upon eosinophil infiltration in airways.
Keywords: Key words Toluene diisocyanate; Asthma; Airway obstruction; Airway hyperreactivity; Eosinophil; Guinea pig
Functional and subcellular organelle changes in isolated rat and human hepatocytes induced by tetrahydroaminoacridine by David K. Monteith; Jeffrey C. Theiss; Jeffrey R. Haskins; F. A. de la Iglesia (pp. 147-156).
Tacrine (tetrahydroaminoacridine) is a reversible cholinesterase inhibitor used for the treatment of Alzheimer’s disease. This drug causes an elevation of serum aminotransferases in a limited population of patients. Several in vivo studies failed to elucidate the mechanism for the enzyme elevation but previous in vitro studies have indicated defects in mitochondrial function. In this study, electron microscopic, histochemical, and confocal microscopy techniques were used with primary hepatocyte cultures from humans and rats to examine the sequence of early cellular changes after tacrine exposure. Changes included ribosome alterations as early as 1 – 2 h following tacrine exposure at concentrations ranging between 0.1 and 1.0 mM. Mitochondrial membrane potential was also altered as indicated by decreased rhodamine 123 uptake with time. Cellular lysosome content increased as indicated by increased staining of fluorescein isothiocyanate (FITC)-conjugated dextran. The results of acid phosphatase histochemistry correlated with the FITC-dextran findings. Additionally, tacrine-related degranulation and vesiculation of the endoplasmic reticulum paralleled the ribosomal and mitochondrial changes. These subcellular changes were reproducible in rat and human hepatocytes, showing for the first time that human hepatocytes can be altered by tacrine. The molecular mechanism of the organelle changes is unkown at this time. Also, the relationship between these subcellular changes in isolated hepatocytes and the transaminase elevation noted in human populations treated with tacrine needs to be clarified.
Keywords: Key words Tetrahydroaminoacridine; Tacrine; Cognex®; Hepatocytes; Toxicity
Characterization of the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in B6C3F1 and DBA/2 mice following single and repeated exposures by D. L. Morris; H. G. Jeong; S. D. Jordan; N. E. Kaminski; M. P. Holsapple (pp. 157-168).
Previous studies have demonstrated that repeated (14 day) administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhances the suppression of humoral immunity in DBA/2 (Ah-low responder) mice relative to the effect seen with identical cumulative doses after a single treatment (cumulative doses of 4.2, 14.0, and 42 mg/kg). In the present studies, we have explored this phenomenon further by determining the status of several specific parameters, which might account for the increase in antibody suppression in the DBA/2 strain following repeated TCDD exposures. Included in these studies was the induction of hepatic and splenic microsomal 7-ethoxyresorufin-o-deethylase (EROD; P4501A1) activity and biodistribution of the administered TCDD into various target organs and tissues. Changes in lymphocyte subpopulations within the spleen were also assessed by flow cytometry following both single and repeated dosing. All studies made use of direct comparisons between DBA/2 (Ah-low responder) and B6C3F1 (Ah-high responder) female mice. Results of these studies demonstrate that the enhanced suppression of humoral immunity in DBA/2 mice following repeated exposure to TCDD is not directly associated with increases in liver microsomal EROD activity and does not appear to be correlated with changes in the pattern of biodistribution or amount of TCDD within the liver or spleen of these animals. In contrast, the most significant changes that occurred following repeated dosing in either strain were observed in the levels of microsomal EROD activity and immune cell ratios within the spleen. This effect was characterized as an increase in microsomal EROD activity, and a corresponding reduction in the numbers of a non-B/non-T cell population in the spleen.
Keywords: Key words TCDD; EROD; humoral immunity; single and repeated exposures; Antibody suppression
A peroxisome proliferator-activated receptor-alpha (PPARα) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARα: implications for species differences in responses to peroxisome proliferators by Jonathan D. Tugwood; Peter R. Holden; Neil H. James; Rebecca A. Prince; Ruth A. Roberts (pp. 169-177).
The peroxisome proliferator class of non-genotoxic rodent hepatocarcinogens cause hepatocyte DNA synthesis, peroxisome proliferation and liver tumours when administered to rats and mice, but fail to induce S-phase or peroxisome proliferation in hepatocytes from other species including guinea-pigs, dogs, and primates including humans. There are compelling data that implicate a nuclear receptor, the peroxisome proliferator-activated receptor-alpha (PPARα) as an important mediator of the toxic and carcinogenic effects of peroxisome proliferators (PPs). We were interested to consider the guinea-pig as a possible model for human responses to these compounds. This manuscript describes the isolation of a full-length cDNA encoding PPARα from guinea-pig liver that is closely related to receptors identified previously in mouse, rat and human. RNA hybridisation experiments suggested that the livers of the PP-responsive rat and mouse contained relatively high levels of PPARα transcripts, whereas in human and guinea-pig liver PPARα mRNA was much less abundant. Functional analyses suggested that the guinea-pig PPARα was able to be activated by PPs. DNA binding studies using in vitro translated proteins showed that the guinea-pig receptor was able to bind specifically to DNA in the presence of the retinoid X receptor (RXR), and transient transfection assays showed that the guinea-pig PPARα was capable of being transcriptionally activated in a concentration-dependent fashion by the PPs Wy-14,643 and nafenopin. Also, in guinea-pig primary hepatocyte cultures, a dominant negative repressor of PPARα ablated the suppression of spontaneous apoptosis by PPs. Taken together, these data show that the `non-responsive' guinea-pig expresses active PPARα in the liver at reduced levels, and may be a useful model for exploring the mechanisms underlying the human response to PPs.
Keywords: Keywords Peroxisome proliferator; Activated receptor; Transcriptional activation; Apoptosis; Species differences
Inhibition of cell-cell communication by methylsulfonyl metabolites of polychlorinated biphenyl congeners in rat liver epithelial IAR 20 cells by Yoshihisa Kato; Kerstin Kenne; Koichi Haraguchi; Yoshito Masuda; Ryohei Kimura; Lars Wärngård (pp. 178-182).
The effects of three polychlorinated biphenyl (PCB) congeners and their six methylsulfonyl (MeSO2)-metabolites on cell communication have been investigated in the scrape-loading/dye-transfer assay in IAR 20 rat liver epithelial cells. The results demonstrated that at non-cytotoxic concentrations 2,2′,4′,5-tetrachlorobiphenyl, 2,2′,4′,5,5′-pentachlorobiphenyl (2,2′,4′,5,5′-pentaCB), 2,2′,4′,5,5′,6-hexachlorobiphenyl (2,2′,4′,5,5′, 6-hexaCB), and their 3- and 4-MeSO2 derivatives completely inhibited the cell communication within 1 h. 4-MeSO2-2,2′,4′,5,5′-pentaCB and 4-MeSO2-2,2′,4′,5, 5′,6-hexaCB appeared to inhibit the cell communication at slightly lower concentration than their parental PCB congeners and 3-MeSO2 derivatives. The results show that 3- and 4-MeSO2 derivatives of the PCB congeners tested inhibit gap junction intercellular communication at about the same potency as their parental compounds. Since inhibition of cell communication is often observed after treatment with many tumor promoters, our findings suggest that the metabolites may also act as tumor promoters.
Keywords: Key words Polychlorinated biphenyl; Methylsulfonyl metabolite; Gap junction intercellular communication; IAR 20 rat liver epithelial cell
Bioactivation of 2-amino-3-methylimidazo[4,5-f ] quinoline (IQ) by prostaglandin H synthase
by G. H. Degen; E. Wolz; M. Gerber; W. Pfau (pp. 183-186).