Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Andersen et al. and Reitz et al. have developed physiologically based pharmacokinetic models for the human metabolism of methylene chloride (dichloromethane; DCM) and have advanced the hypothesis that the carcinogenicity of DCM is related to target organ metabolism of DCM by glutathione S-transferase (GST). The models included physiological parameters appropriate for humans at rest and metabolic parameters based on average rates of DCM metabolism. Increasing the model parameters describing cardiac output, alveolar ventilation, and blood flows to tissues from resting values to values consistent with light work conditions, and assuming a 25 ppm exposure for an 8-hr work day, increases the estimated GST-metabolized dose for human liver by a factor of 2.9 compared to the GST-metabolized does estimated of Reitz et al. These modifications also increase the GST-metabolized dose to the lung by 2.4-fold. If the model is also modified to reflect individual variation in DCM metabolism (in addition to the modifications for light work conditions), the estimated GST-metabolized dose for human liver ranges from 0 to as much as 5.4-fold greater than the dose estimated by Reitz et al. The GST-metabolized dose to the lung ranges from 0 to as much as 3.6-fold greater than the dose estimated by Reitz et al. These results indicate that some occupationally-exposed individuals may receive GST-metabolized doses several-fold greater than the Reitz et al. human dose estimates.
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PMID:The impact of exercise and intersubject variability on dose estimates for dichloromethane derived from a physiologically based pharmacokinetic model. 812 9

Dichloromethane (DCM) (methylene chloride; CH2Cl2) is metabolized via a glutathione S-transferase-mediated pathway to formaldehyde (HCHO), a mutagenic compound that could play a role in the carcinogenic effects of DCM observed in the liver and lungs of B6C3F1 mice at 2000 and 4000 ppm. Mice but not hamsters formed DNA-protein cross-links (DPX) in the liver at DCM concentrations ranging from approximately 500 to 4000 ppm. The formation of DPX was a nonlinear function of the airborne concentration of DCM. In addition, mice exposed to DCM (6 hr/day, 3 days) at concentrations ranging from approximately 1500 to 4000 ppm showed an increased rate of DNA synthesis in the lung indicating cell proliferation, but increased cell turnover was not detected in mouse lung at exposure concentrations of 150 or 500 ppm. Hamsters showed no evidence of cell proliferation in the lung at any concentration, and cell proliferation was not apparent in the livers of either mice or hamsters. An extended physiologically based pharmacokinetic (PBPK) model for DPX formation in mouse liver was developed, based on a published PBPK model for DCM (Andersen, M.E., Clewell, H.J., III, Gargas, M.L., Smith, F.A., and Reitz, R.H. (1987). Toxicol. Appl. Pharmacol. 87, 185-205). The extended PBPK model was fitted to the DPX data using the PBPK model-estimated area under the curve for DCM in mouse liver as the independent variable. Parameter estimates for HCHO disposition in the livers of mice exposed to dichloromethane were similar to previously published estimates for HCHO disposition in the nasal mucosa of rats exposed to formaldehyde. Using the extended PBPK model, estimates were made of the yields of DPX presumably formed in mouse liver at the DCM concentrations used in a bioassay (Mennear, J.H., McConnell, E.E., Huff, J.E., Renne, R.A., and Giddens, E. (1988). Ann. NY Acad. Sci. 534, 343-351). The tumor incidence data in mice were fitted to the DPX yields and to the airborne concentration of DCM as alternative measures of exposure using the linearized multistage (LMS) model. The two dose measures yielded similar maximum likelihood estimates for the cancer risk at concentrations from 10 to 100 ppm, but the upper 95% confidence limit on the risk was reduced by two orders of magnitude when DPX rather than the airborne concentration was used as the measure of exposure. The results demonstrate that an internal dosimeter such as DPX can markedly improve the precision of low-dose risk estimates, while having only a minor effect on the maximum likelihood estimates calculated with the LMS model.
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PMID:DNA-protein cross-links (DPX) and cell proliferation in B6C3F1 mice but not Syrian golden hamsters exposed to dichloromethane: pharmacokinetics and risk assessment with DPX as dosimeter. 899 46

We previously reported that a velvetleaf (Abutilon theophrasti Medic) biotype found in Maryland was resistant to atrazine because of an enhanced capacity to detoxify the herbicide via glutathione conjugation (JW Gronwald, Andersen RN, Yee C [1989] Pestic Biochem Physiol 34: 149-163). The biochemical basis for the enhanced atrazine conjugation capacity in this biotype was examined. Glutathione levels and glutathione S-transferase activity were determined in extracts from the atrazine-resistant biotype and an atrazine-susceptible or "wild-type" velvetleaf biotype. In both biotypes, the highest concentration of glutathione (approximately 500 nanomoles per gram fresh weight) was found in leaf tissue. However, no significant differences were found in glutathione levels in roots, stems, or leaves of either biotype. In both biotypes, the highest concentration of glutathione S-transferase activity measured with 1-chloro-2,4-dinitrobenzene or atrazine as substrate was in leaf tissue. Glutathione S-transferase measured with 1-chloro-2,4-dinitrobenzene as substrate was 40 and 25% greater in leaf and stem tissue, respectively, of the susceptible biotype compared to the resistant biotype. In contrast, glutathione S-transferase activity measured with atrazine as substrate was 4.4- and 3.6-fold greater in leaf and stem tissue, respectively, of the resistant biotype. Kinetic analyses of glutathione S-transferase activity in leaf extracts from the resistant and susceptible biotypes were performed with the substrates glutathione, 1-chloro-2,4-dinitrobenzene, and atrazine. There was little or no change in apparent K(m) values for glutathione, atrazine, or 1-chloro-2,4-dinitrobenzene. However, the V(max) for glutathione and atrazine were approximately 3-fold higher in the resistant biotype than in the susceptible biotype. In contrast, the V(max) for 1-chloro-2,4-dinitrobenzene was 30% lower in the resistant biotype. Leaf glutathione S-transferase isozymes that exhibit activity with atrazine and 1-chloro-2,4-dinitrobenzene were separated by fast protein liquid (anion-exchange) chromatography. The susceptible biotype had three peaks exhibiting activity with atrazine and the resistant biotype had two. The two peaks of glutathione S-transferase activity with atrazine from the resistant biotype coeluted with two of the peaks from the susceptible biotype, but peak height was three- to fourfold greater in the resistant biotype. In both biotypes, two of the peaks that exhibit glutathione S-transferase activity with atrazine also exhibited activity with 1-chloro-2,4-dinitrobenzene, with the peak height being greater in the susceptible biotype. The results indicate that atrazine resistance in the velvetleaf biotype from Maryland is due to enhanced glutathione S-transferase activity for atrazine in leaf and stem tissue which results in an enhanced capacity to detoxify the herbicide via glutathione conjugation.
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PMID:Atrazine Resistance in a Velvetleaf (Abutilon theophrasti) Biotype Due to Enhanced Glutathione S-Transferase Activity. 1666 37