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The roles of glutathione and ascorbate in chromium (VI)-induced carcinogenesis in vivo.

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Call No.	QD181.C7 Y93 1997
Author	Yuann, Jeu-Ming P.
Title	The roles of glutathione and ascorbate in chromium (VI)-induced carcinogenesis in vivo.
Date	1997
Abstract	Chromium(VI) is a human carcinogen and causes DNA damage following reduction by intracellular reductants. In order to explore the effects of intracellular reductants on the carcinogenicity of Cr(VI), the roles of glutathione and ascorbate in Cr(VI)-induced metabolism and DNA damage were investigated in 18-day chick embryos and Osteogenic Disorder Shionogi (ODS) rats in vivo. The effects of varying levels of each of these reductants experimentally on generation of Cr(V) species and correlation with levels of Cr-DNA adducts and 8-OH-dG were specifically explored. A transient Cr(V) species was detected in the liver, but not red blood cells, of 18-day chick embryos treated with Cr(VI) (sodium dichromate, 0.05-0.20 mmol/kg body weight). High levels of Cr-DNA adducts were only observed in the livers of 18-day chick embryos following treatment with Cr(VI). In ODS rats treated with low ascorbate (50 ppm), the reduction of Cr(VI) was significantly suppressed in liver and kidney ultrafiltrates as compared with that of rats treated with high ascorbate (800 ppm). A Cr(V) EPR signal was observed in conjunction with Cr-DNA binding after i.p. injection of ODS rats with Cr(VI) (sodium dichromate, 10 mg/kg). Both the intensity of the Cr(V) EPR signal and the Cr-DNA binding was about 2-fold higher in the liver than in the kidney regardless of the levels of ascorbate in ODS rats, while the overall levels of chromium were similar in both organs. Cr-uptake into the liver and kidney was lower in the high ascorbate rats than in the low ascorbate ones. 8-OH-dG levels in both organs were not affected by either ascorbate or Cr(VI) treatments in ODS rats. In ODS rats treated with glutathione modulating agents, Cr(V) EPR signal intensity was significantly higher in the liver when glutathione levels were decreased by phorone, whereas Cr(V) EPR intensity was higher in the kidney of ODS rats depleted of glutathione by L-buthionine-S,R-sulfoximine (BSO). N-Acetyl-L-cysteine (NAC), however, increased Cr-DNA binding in both the liver and kidney of rats regardless of ascorbate levels. 8-OH-dG levels were not affected in the kidney of ODS rats following treatment with both BSO and Cr(VI). These results indicate that ascorbate, which has previously been shown to be the principal reductant of Cr(VI) in rat cytosol ultrafiltrates in vitro, does not play the principal role in formation of Cr(V), Cr-DNA binding, and 8-0H-dG in vivo. Similarly, glutathione levels do not correlate with generation of these types of DNA damage. Therefore, reductants other than ascorbate and glutathione, e.g. cysteine, may be more important in terms of the formation of Cr(V) and subsequent DNA damage.
Description	1 online resource (xvii, 155 leaves) : illustrations
Format	application/pdf
Advisor	Hamilton, Joshua W.
Subject	Chromium -- Toxicity testing. ; Glutathione. ; Vitamin C -- Physiological effect. ; Carcinogenesis. ; DNA damage.
College	Dartmouth College -- Department of Chemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	In Copyright. This material is protected by copyright and/or related rights. You are free to use this material in any way that is permitted by copyright law that applies to your use. For other uses, you need to obtain permission from the rights-holder(s). http://rightsstatements.org/page/InC/1.0/
DOI	https://doi.org/10.1349/ddlp.2930

Title	yuann1997 1
Full Text	The Roles of Glutathione and Ascorbate in Chromium(VI)-Induced Carcinogenesis In Vivo A Thesis Submitted to the Faculty in partial fiilfillment of the requirements for the degree of Doctor of Philosophy in Department of Chemistry by Jeu-Ming P. Yuann DARTMOUTH COLLEGE Hanover, NH 03755 June 5, 1997

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The roles of glutathione and ascorbate in chromium (VI)-induced carcinogenesis in vivo.

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