Exploration of the Transformation Potential of a Unique Male Rat Protein Alpha2u-Globulin Using Hamster Embryonic Cells

Several environmentally and socially important chemicals such as d-limonene and unleaded gasoline have been demonstrated to induce alphas-globulin (a2u) nephropathy in male rats. Substantial progress has been made in characterizing the biological effects of these chemicals on the kidney and in further defining prerequisite events in the pathogenesis of this syndrome. The ot2u increase in the kidney is hypothesized to be the proximal event in the toxicologic and tumorigenic sequelae associated with administration of these xenobiolics over the male rat's lifetime rather than a direct effect of the administered chemical. The administered chemical appears to simply mediate the increase in ot2u concentration in the kidney. To further investigate the properties of a2u, this protein was tested in the pH 6.7 Syrian hamster embryo (SHE) cell transformation assay. The a2u caused morphological transformation in these cells, whereas another protein, bovine serum albumin, did not induce transformation at equimolar concentrations, suggesting a protein-specific phenomenon. Neither rf-limonene nor trimethylpentane (a causarcomponent in unleaded gasoline) induced SHE cell transformation. These results support the hypothesis that a2u increase in proximal convoluted tubules may directly cause renal tumorigenesis in male rats. The SHE cell transformation assay may be a useful tool for mechanistic studies of this syndrome.

[1]  J. Roh,et al.  Clastogenicity of methapyrilene hydrochloride in cultured Chinese hamster cells. , 1994, Mutation research.

[2]  M. Garriott,et al.  The evaluation of methapyrilene for bacterial mutation with metabolic activation by Aroclor-induced, methapyrilene-induced and noninduced rat-liver S9. , 1993, Mutation research.

[3]  D. Clive,et al.  The potent hepatocarcinogen methapyrilene induces mutations in L5178Y mouse lymphoma cells in the apparent absence of DNA adduct formation. , 1991, Mutation research.

[4]  R. Takigiku,et al.  d-Limonene-induced male rat-specific nephrotoxicity: evaluation of the association between d-limonene and alpha 2u-globulin. , 1989, Toxicology and applied pharmacology.

[5]  J. Poiley,et al.  An interlaboratory comparison of enhanced morphological transformation of Syrian hamster embryo cells cultured under conditions of reduced bicarbonate concentration and pH. , 1989, Mutation research.

[6]  W. Lijinsky,et al.  Lack of binding of methapyrilene and similar antihistamines to rat liver DNA examined by 32P postlabeling. , 1988, Cancer research.

[7]  Y. Oshiro,et al.  Experimental design for the C3H/10T½ CL8 cell transformation assay , 1988, Journal of applied toxicology : JAT.

[8]  J. Swenberg,et al.  Site-specific renal cytotoxicity and cell proliferation in male rats exposed to petroleum hydrocarbons. , 1987, Laboratory investigation; a journal of technical methods and pathology.

[9]  E. Lock,et al.  2,2,4-Trimethylpentane-induced nephrotoxicity. I. Metabolic disposition of TMP in male and female Fischer 344 rats. , 1987, Toxicology and applied pharmacology.

[10]  R. Leboeuf,et al.  Enhanced morphological transformation of early passage Syrian hamster embryo cells cultured in medium with a reduced bicarbonate concentration and pH. , 1987, Carcinogenesis.

[11]  E. Lock,et al.  Alpha 2U-globulin: measurement in rat kidney following administration of 2,2,4-trimethylpentane. , 1986, Toxicology.

[12]  A. Pesce,et al.  Proteinuria: An Integrated Review , 1979 .

[13]  J. Figueiredo,et al.  Renal filtration, transport, and metabolism of low-molecular-weight proteins: a review. , 1979, Kidney international.

[14]  S. E. Lane,et al.  Synergistic effect of glucocorticoids and androgens on the biosynthesis of a sex-dependent protein in the male rat. , 1971, Biochimica et biophysica acta.

[15]  M. Andersen,et al.  Development of a mechanism-based dosimetry model for 2,4,4-trimethyl-2-pentanol-induced alpha 2u-globulin nephropathy in male Fischer 344 rats. , 1995, Fundamental and Applied Toxicology.

[16]  J. Ashby,et al.  Mutation spectrum of a binary mixture of mutagens (methapyrilene and sodium azide) in strain TA1535 of Salmonella. , 1994, Mutation research.

[17]  L. Gold,et al.  Mitogenesis, mutagenesis, and animal cancer tests. , 1991, Progress in clinical and biological research.

[18]  C. Alden,et al.  15 – Urinary System , 1991 .

[19]  Ames Bn,et al.  Mitogenesis, mutagenesis, and animal cancer tests. , 1991 .

[20]  J. Swenberg,et al.  The comparative pathobiology of α2u-globulin nephropathy , 1989 .

[21]  J. Ashby,et al.  Weak and unexpected mutagenicity to Salmonella of the rat hepatocarcinogen methapyrilene. , 1988, Environmental and molecular mutagenesis.

[22]  M. E. Frazier,et al.  Transformation of Syrian hamster embryo cells by synfuel mixtures. , 1983, Journal of toxicology and environmental health.

[23]  T H Shepard,et al.  National toxicology program. , 1981, Teratology.

[24]  R. Pienta.  Transformation of Syrian Hamster Embryo Cells by Diverse Chemicals and Correlation with Their Reported Carcinogenic and Mutagenic Activities , 1980 .

[25]  Zontine Wj.  The urinary system. , 1975, Modern veterinary practice.