Glutathione and glutathione S-transferases in the salmonella mammalian-microsome mutagenicity test

Summer, Karl‐Heinz; Göggelmann, W.; Greim, Helmut

doi:10.1016/0027-5107(80)90018-4

Cited by 47 publications

(12 citation statements)

References 13 publications

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“…One study obtained more than 75% hair regrowth at the end of 20 weeks of DNCB therapy in 65% of the treated human AA patients. However, Summer et al (46) reported that DNCB was mutagenic against Salmonella typhimurium in the Ames test and should no longer be used. DNCB was tested at one point in DEBR rats with a hair regrowth response; however, the inflammatory response was so severe that the investigators abandoned the study after a few applications.…”

Section: Dinitrochlorobenzenementioning

confidence: 99%

The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results

Sun

Silva

McElwee

et al. 2008

Experimental Dermatology

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The C3H ⁄ HeJ inbred mouse strain and the Dundee Experimental Bald Rat (DEBR) strain spontaneously develop adult onset alopecia areata (AA), a cell-mediated disease directed against actively growing hair follicles. The low frequency of AA and the inability to predict the stage of AA as it evolves in the naturally occuring C3H ⁄ HeJ model of AA can be converted into a highly predictable system by grafting full thickness skin from AA-affected mice to normal haired mice of the same strain. The rat DEBR model develops spontaneous AA at a higher frequency than in the mouse model but they are more expensive to use in drug studies owing to their larger size. Regardless of the shortcomings of either model, these rodent models can be used succesfully to screen novel or approved drugs for efficacy to treat human AA. As the pathogenesis of AA follows the canonical lymphocytic co-stimulatory cascade in the mouse AA model, it can be used to screen compounds potentially useful to treat a variety of cellmediated diseases. Efficacy of various agents can easily be screened by simply observing the presence, rate, and cosmetic acceptability of hair regrowth. More sophisticated assays can refine how the drugs induce hair regrowth and evaluate the underlying pathogenesis of AA. Some drugs commonly used to treat human AA patients work equally as well in both rodent models validating their usefulness as models for drug efficacy and safety for humanAA.Key words: alopecia areata -animal modeldinitrochlorobenzene -diphenylcyclopropenone -reviewsquaric acid dibutyl esterase -treatment Please cite this paper as: The C3H ⁄ HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results.

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Section: Dinitrochlorobenzenementioning

confidence: 99%

The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results

Sun

Silva

McElwee

et al. 2008

Experimental Dermatology

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“…Enzymes ofthe GSH S-transferase theta class, especially rat GSH S-transferase 5-5, have been shown to be proficient in the conjugation of CH2Cl2 (9). Methylobacterium DM4 has been demonstrated to have a high level of a theta class enzyme that can be effective in conjugating CH2Cl2 (17), and the possibility exists that S. typhimurium contains such an enzyme for activating dihalomethanes and 1,2-dihaloethanes (17,18). Our efforts to demonstrate the GSH-dependent conjugation through depletion of GSH within the cells were not particularly successful, and we also considered the possibility that the putative S-(l-halomethyl)GSH products might be unable to cross cell membranes.…”

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confidence: 99%

Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes.

Thier

Taylor

Pemble

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

179

166

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Dihalomethanes can produce liver tumors in mice but not in rats, and concern exists about the risk of these compounds to humans. Glutathione (GSH) conjugation of dihalomethanes has been considered to be a crifical event in the bioactivation process, and risk assessment is based upon this premise; however, there is little experimental support for this view or information about the basis of genotoxicity. A plasmid vector containing rat GSH S-transferase 5-5 was transfected into the SalmoneUla typhimurium tester strain TA1535, which then produced active enzyme. The transfected bacteria produced base-pair revertants in the presence ofethylene dihalides or dihalomethanes, in the order CH2Br2 > CH2BrCl > CH2CI2. However, revertants were not seen when cells were exposed to GSH, CH2Br2, and an amount of purified GSH S-ransferase 5-5 (20-fold excess in amount of that expressed within the cells). HCHO, which is an end product of the reaction of GSH with dihalomethanes, also did not produce mutations. S-(1-Acetoxymethyl)GSH was prepared as an analog of the putative S-(1-halomethyl)GSH reactive intermediates. This analog did not produce revertants, consistent with the view that activation of dihalomethanes must occur within the bacteria to cause genetic damage, presenting a model to be considered in studies with mammalian cells. S-(1-Acetoxymethyl)GSH reacted with 2'-deoxyguanosine to yield a major adduct, identified as S-[l-(N2-deoxyguanosinyl)methyl]GSH.

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“…S-9 fraction was prepared from the liver of rats pretreated with a single oral dose of 500 mg Clophen A 50 per kg, 5 days prior to the experiments [11].…”

Section: Bacterial Mutagenicity Testmentioning

confidence: 99%

Contact Allergy as a Therapeutic Tool for Alopecia Areata: Application of Squaric Acid Dibutylester

et al. 1980

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Squaric acid dibutylester (SADBE), a potent contact allergen, was tested for mutagenicity in the bacterial plate incorporation assay (Ames test), in the presence and absence of mammalian microsomes. In contrast to dinitrochlorobenzene which is mutagenic in this test, SADBE was found not to be mutagenic. In 53 patients with extensive or total alopecia areata, SADBE dissolved in acetone was applied weekly to one side of the head, the other side serving as control. In 46 patients (87%), hair regrew either exclusively on the treated side, or considerably faster and denser on this side. In some patients, continuous treatment failed to maintain the response. Persistent response was observed in 37 patients (70%). These results are essentially the same as those obtained with DNCB. Therefore, contact allergy is proposed as a therapeutic concept for alopecia areata.

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Glutathione and glutathione S-transferases in the salmonella mammalian-microsome mutagenicity test

Cited by 47 publications

References 13 publications

The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results

The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results

Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes.

Contact Allergy as a Therapeutic Tool for Alopecia Areata: Application of Squaric Acid Dibutylester

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