A physiological model for ligand-induced accumulation of alpha 2u globulin in male rat kidney: roles of protein synthesis and lysosomal degradation in the renal dosimetry of 2,4,4-trimethyl-2-pentanol.

A physiologically based pharmacokinetic (PBPK) model was constructed for the disposition of 2,4,4-trimethyl-2-pentanol (TMP-2-OH) in male rats and its induction of accumulation of renal alpha2u-globulin (alpha2u). The model included diffusion-restricted delivery of TMP-2-OH to compartments representing liver, lung, fat, kidney, GI tract, aggregated rapidly perfused tissues, and aggregated slowly perfused tissues. Metabolism by oxidation and glucuronidation was included for liver and kidneys. Rates of hepatic alpha2u production and resorption by renal proximal tubules were taken from the literature. Degradation of liganded alpha2u by renal lysosomal cathepsins was modeled with a Km value corresponding to the measured 30% reduction in proteolytic efficiency and with free and bound forms of alpha2u competing for access to the enzymes. Increased pinocytotic uptake of alpha2u into the kidney induces cathepsin activity. A model that ascribed renal alpha2u accumulation solely to reduced lysosomal proteolysis failed to reproduce the observed accumulation. The model could reproduce experimental observations if a transient increase in hepatic synthesis of alpha2u, stimulated by the presence of liganded alpha2u in the blood, and accelerated secretion of the protein from the liver were assumed. This model reproduces time course data of blood and kidney TMP-2-OH and renal alpha2u concentrations, suggesting that renal accumulation of alpha2u is not simply a consequence of reduced proteolytic degradation but may also involve a transient increase in hepatic alpha2u production. The model predicts increased delivery of TMP-2-OH to the kidney and consequent increased renal production of potentially toxic TMP-2-OH metabolites than would be the case if no alpha2u were present. Induced lysosomal activity and increased production of toxic metabolites may both contribute to the nephrotoxicity observed in male rats exposed to an alpha2u ligand or its precursor.

[1]  J Siemiatycki,et al.  Associations between several sites of cancer and twelve petroleum-derived liquids. Results from a case-referent study in Montreal. , 1987, Scandinavian journal of work, environment & health.

[2]  R. Armstrong,et al.  Distribution of cardiac output during diurnal changes of activity in rats. , 1991, The American journal of physiology.

[3]  R. Lutz,et al.  A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat. , 1977, Drug metabolism and disposition: the biological fate of chemicals.

[4]  B. D. Garg,et al.  Hydrocarbon-induced hyaline droplet nephropathy in male rats during senescence. , 1988, Toxicology and applied pharmacology.

[5]  J. Swenberg,et al.  A comparison of European High Test gasoline and PS-6 unleaded gasoline in their abilities to induce alpha 2u-globulin nephropathy and renal cell proliferation. , 1992, Toxicology letters.

[6]  D. Dietrich,et al.  The Presence of α2u-Globulin Is Necessary for d-Limonene Promotion of Male Rat Kidney Tumors , 1991 .

[7]  A. E. Sippel,et al.  Effect of thyroid hormones on the level of the hepatic mRNA for alpha2u globulin. , 1976, Biochemistry.

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

[9]  D. Miller,et al.  Mechanisms mediating renal secretion of organic anions and cations. , 1993, Physiological reviews.

[10]  M E Andersen,et al.  Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. , 1989, Toxicology and applied pharmacology.

[11]  O. Neuhaus,et al.  Dietary control of the renal reabsorption and excretion of α2u-globulin , 1979 .

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

[13]  A. Roy,et al.  Androgenic Control of a Sex-dependent Protein in the Rat , 1967, Nature.

[14]  B. Fowler,et al.  Cadmium-Metallothionein nephropathy: relationships between ultrastructural/biochemical alterations and intracellular cadmium binding. , 1984, The Journal of pharmacology and experimental therapeutics.

[15]  M C Kohn,et al.  The importance of anatomical realism for validation of physiological models of disposition of inhaled toxicants. , 1997, Toxicology and applied pharmacology.

[16]  A. B. Maunsbach.  Isolation of kidney lysosomes. , 1974, Methods in enzymology.

[17]  Robert F. Pitts,et al.  Physiology of the Kidney and Body Fluids , 1963 .

[18]  J A Swenberg,et al.  Characteristics of chemical binding to alpha 2u-globulin in vitro--evaluating structure-activity relationships. , 1991, Toxicology and applied pharmacology.

[19]  L. Lehman-Mckeeman,et al.  Alpha 2u-globulin is the only member of the lipocalin protein superfamily that binds to hyaline droplet inducing agents. , 1992, Toxicology and applied pharmacology.

[20]  J. Huff,et al.  Cellular and molecular mechanisms of chemically induced renal carcinogenesis. , 1991, Renal failure.

[21]  M C Kohn,et al.  SCoP: an interactive simulation control program for micro- and minicomputers. , 1986, Bulletin of mathematical biology.

[22]  E. Khairallah.  IN VIVO DETERMINATION OF RATES OF PROTEIN DEGRADATION IN LIVERS OF MEAL-FED RATS: IMPLICATIONS OF AMINO ACID COMPARTMENTATION , 1978 .

[23]  M. Delp,et al.  Physiological Parameter Values for Physiologically Based Pharmacokinetic Models , 1997, Toxicology and industrial health.

[24]  J. Swenberg,et al.  Biochemical Mechanisms and Pathobiology of α2u-Globulin Nephropathy , 1990 .

[25]  B. D. Garg,et al.  Accumulation of alpha 2u-globulin in the renal proximal tubules of male rats exposed to unleaded gasoline. , 1987, Toxicology and applied pharmacology.

[26]  K. Chan,et al.  Sequential passage of alpha2mu-globulin through the hepatic endoplasmic reticulum and Golgi apparatus during secretion. , 1978, Biochimica et biophysica acta.

[27]  L. Lehman-Mckeeman.  Lysosomal degradation of ?2u-globulin and ?2u-globulin-xenobiotic conjugates*1 , 1990 .

[28]  R. Melnick,et al.  An alternative hypothesis on the role of chemically induced protein droplet (alpha 2u-globulin) nephropathy in renal carcinogenesis. , 1992, Regulatory toxicology and pharmacology : RTP.

[29]  P. Grandjean,et al.  Risk of cancer and exposure to gasoline vapors. , 1997, American journal of epidemiology.

[30]  J. Swenberg,et al.  Promoting effects of unleaded gasoline and 2,2,4-trimethylpentane on the development of atypical cell foci and renal tubular cell tumors in rats exposed to N-ethyl-N-hydroxyethylnitrosamine. , 1989, Cancer research.

[31]  O. Neuhaus,et al.  Age-dependent changes in the excretion of urinary proteins by the rat. , 1978, Nephron.

[32]  P. Enck,et al.  Stress effects on gastrointestinal transit in the rat. , 1989, Gut.

[33]  O. Neuhaus,et al.  Urinary excretion of alpha 2 mu-globulin and albumin by adult male rats following treatment with nephrotoxic agents. , 1981, Nephron.

[34]  M. D. Feezor,et al.  A block organized model builder , 1994 .

[35]  S. Uwagawa,et al.  α2u-Globulins in the urine of male rats: a reliable indicator for α2u-globulin accumulation in the kidney , 1996 .

[36]  Knut Schmidt-Nielsen,et al.  Animal Physiology: Adaptation and Environment , 1985 .

[37]  N. Read,et al.  Adaptation of hydrogen analysis to measure stomach to caecum transit time in the rat. , 1987, Gut.

[38]  J. Swenberg,et al.  Elevated proliferation of proximal tubule cells and localization of accumulated alpha 2u-globulin in F344 rats during chronic exposure to unleaded gasoline or 2,2,4-trimethylpentane. , 1989, Toxicology and applied pharmacology.

[39]  S. Ohkuma,et al.  SOME ASPECTS OF THE INTRACELLULAR BREAKDOWN OF EXOGENOUS AND ENDOGENOUS PROTEINS , 1978 .

[40]  Glucocorticoid induction of hepatic alpha2u-globulin synthesis and messenger RNA level in castrated male rats in vivo. , 1978, The Journal of biological chemistry.

[41]  H. Macfarland,et al.  A Chronic Inhalation Study with Unleaded Gasoline Vapor , 1984 .

[42]  P. Dejours.  Principles of Comparative Respiratory Physiology , 1975 .

[43]  C. Viau,et al.  Isoparaffinic solvent-induced nephrotoxicity in the rat. , 1986, Toxicology.

[44]  L. Greenbaum.  12 Cathepsins and Kinin-Forming and -Destroying Enzymes , 1971 .

[45]  R A Freeman,et al.  A physiologically based model for gastrointestinal absorption and excretion of chemicals carried by lipids. , 1993, Risk analysis : an official publication of the Society for Risk Analysis.

[46]  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.

[47]  P. Feigelson,et al.  CHAPTER 11 – Multihormonal Control of the Messenger RNA for the Hepatic Protein α2u Globulin , 1978 .

[48]  W. Ward,et al.  LYSOSOMAL PROCESSING OF INTRACELLULAR PROTEIN IN RAT LIVER AND ITS GENERAL REGULATION BY AMINO ACIDS AND INSULIN , 1978 .

[49]  O. Neuhaus.  Renal Reabsorption of Low Molecular Weight Proteins in Adult Male Rats: α2u-Globulin , 1986 .

[50]  D. Wolf,et al.  Methyltert-Butyl Ether Causes α2u-Globulin Nephropathy and Enhanced Renal Cell Proliferation in Male Fischer-344 Rats , 1997 .

[51]  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.

[52]  A. Ojajärvi,et al.  Renal cell cancer and occupational exposure to chemical agents. , 1991, Scandinavian journal of work, environment & health.