Historical Perspectives on Conjugation Dependent Bioactivation of Foreign Compounds James A Miller and Young Joon Surh

Metabolic Research Leading to Conjugation-Dependent Bioactivation of 4-Dimethylaminoazobenzene and 2-Acetylaminofluorene 1 B. Covalent Binding of Carcinogens to Tissue Macromolecules 2 C. Hepatic Microsomal Metabolism of Carcinogens and Its Induction by Unrelated Chemicals 3 D. Conjugation-Dependent Bioactivation of DAB and AAF 4 II. Important Observations Leading to Bioactivation of Foreign Compounds via Glutathione Conjugation, Methylation, and Epoxide Formation D. Epoxide Formation and...

Formation and Fate of Nephrotoxic and Cytotoxic Glutathione SConjugates Cysteine Conjugate 3Lyase Pathway

Wolfgang Dekant, Spyridon Vamvakas, and M. W. Anders II. Biosynthesis of Toxic Glutathione S-Conjugates 116 A. Enzymatic Processing of Toxic Glutathione S-Conjugates 120 B. Physiological Disposition of Toxic Glutathione S-Conjugates 123 IV. Bioactivation of Cytotoxic and Nephrotoxic Cysteine S-Conjugates 131 A. Unstable Thiols as Products of 3-Lyase-CataIyzed Metabolism 133 B. Chemically Stable Thiols as Products of 8-Lyase-Catalyzed Metabolism 136 V. Cellular Effects of Cytotoxic and...

Cytotoxicity in Vitro

The toxicity of a number of haloalkenyl -conjugates has been studied in vitro in renal slices, in isolated proximal tubules, in freshly isolated rat proximal tubule cells, and in LLC-PK, cells, a cultured line of porcine kidney cells. In isolated rat renal cortical slices, -conjugates increased the production of the f3-lyase cleavage products pyruvate and ammonia and generated a reactive moiety that inhibited the activity of the renal 7-aminohippurate and tetraethylammonium transport systems...

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And, through the mediation of the Ah or TCDD receptor, is associated with induction by planar aromatic compounds (Paulson et al., 1990), such as polycyclic aromatic hydrocarbons. However, whereas in CYP1A1, the XRE is multiple (Denison et al., 1988), GST lb has only one. An additional sequence also associated with induction, namely the antioxidant responsive element (ARE), appears to play the more important role (Rushmore et al., 1991). The ARE sequence, GTGACAAAGC, contains an API-like element...

Glutathione Mercaptides as Transport Forms of Metals N Ballatori

Formation of Glutathione Mercaptides 272 III. Roles of Glutathione in the Disposition and Toxicity of Metals 274 A. Mobilization and Delivery of Metals between Ligands 274 B. Transport of Metals across Cell Membranes as Glutathione Complexes 277 C. Cellular Uptake of Glutathione and Glutathione Adducts Inter- and Intraorgan Metabolism of Glutathione-Metal Complexes 282 D. Glutathione as Reductant or Cofactor for Redox Reactions of Metal Compounds 288

Enzymes That Cleave the Thioether Bond of 5Substituted Cysteines

A number of enzymes are known to catalyze the cleavage of the proximal (i.e., the S C3) bond of S-substituted cysteines (RSCH2CH(NH2) C02H). In each case, the products are pyruvate (CH3C0C02H), ammonia (NH3), and RSH. For example, an important enzyme in the pathway to formation of methionine in plants and microorganisms is 3-cystathionase, which catalyzes the conversion of cystathionine (R CH2CH2CH(NH2)C02H) to homocysteine, pyruvate, and ammonia (e.g., Wijesundera and Woods, 1962 Flavin and...

Bioactivation of Thiols by One Electron Oxidation Rex Munday

Reactions of the Thiyl Radical 238 A. Formation of Disulfide via the Disulfide Radical Anion 238 E. Addition to Unsaturated Compounds 242 III. Pathways for One-Electron Oxidation of Thiols 242 A. Metal-Catalyzed Oxidation of Thiols 242 B. Oxidation of Thiols by Hemoglobin 244 C. Oxidation of Thiols by Free Radicals 244 D. Oxidation of Thiols by Quinones and by Alloxan 245 IV. Structural Effects on One-Electron Oxidation of Thiols 249 V. Beneficial and Harmful Effects of Thiyl Radical...

Design of Prodrugs Directed toward Glutamine Transaminase KCysteine 5Conjugate Lyase in the Kidney

According to a recent survey approximately 1,040,000 new cancer cases are calculated to have occurred in the United States in 1990. Of these, 24,000 are estimated to have arisen in the kidneys Henderson et al., 1991 . Although in absolute numbers the incidence of kidney cancer is relatively small compared to the overall incidence of cancer in the general population, kidney cancer is nevertheless a serious problem. Metastatic renal cell carcinoma is essentially resistant to all currently used...