Skip to main content
Log in

Induction of peroxisomal β-oxidation and P-450 4A-dependent activities by pivalic and trichloroacetic acid in rat liver and kidney

  • Original Investigation
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

The influence of pivalic acid (PIV), a compound often used to make pro-drugs, and of the structurally related trichloroacetic acid (TCA), on several hepatic and renal enzymes was investigated in Sprague-Dawley rats, following a 4-day treatment period. The PIV and TCA treatments resulted in a similar and selective induction (2–3 times) of peroxisomal palmitoyl-CoA oxidase and the cytochrome P-450 4A dependent microsomal (ω)- and (ω-1)-lauric acid activities, both in liver and kidney. Western blot analysis of liver and kidney microsomes from PIV- and TCA-treated rats, using antibody to the P-450 4A1, revealed induction of members of the P-450 4A subfamily. These results suggest that PIV, like TCA, is a renal and hepatic peroxisome proliferator in rats, and further support the previously indicated close association between the peroxisomal fatty acid β-oxidation enzymes and microsomal P-450 4A subfamily enzymes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Barker SA, Monti JA, Christian ST, Benington F, Morin RD (1980) 9-Diazomethylanthracene as a new fluorescence and ultraviolet label for spectrometric detection of picomole quantities of fatty acids by high-pressure liquid chromatography. Anal Biochem 107: 116–123

    Article  PubMed  CAS  Google Scholar 

  • Binderup E, Gotfrendsen WO, Roholt J (1971) Orally active cefaloglycin esters. J Antibiot 24: 767–773

    PubMed  CAS  Google Scholar 

  • Bronfman M, Inestrosa NC, Leighton F (1979) Fatty acid oxidation by human liver peroxisomes. Biochem Biophys Res Commun 88: 1030–1036

    Article  PubMed  CAS  Google Scholar 

  • Bull RJ, Sanchez IM, Nelson MA, Larson JL, Lansig AJ (1990) Liver tumor induction in B6C3F1 mice by dichloroacetate and trichloro-acetate. Toxicology 63: 341–359

    Article  PubMed  CAS  Google Scholar 

  • Butterworth BE, Bermudez E, Smith-Oliver T, Earle L, Cattley R, Martin J, Popp JA, Strom S, Jirtle R, Michalopoulos G (1984) Lack of genotoxic activity of di(2-ethylhexyl)phtalate (DEHP) in rat and human hepatocytes. Carcinogenesis 5: 1329–1335

    Article  PubMed  CAS  Google Scholar 

  • De Angelo AB, Daniel FB (1992) An evaluation of the carcinogenicity of the chloroacetic acids in the male F344 rat. Toxicologist 12:206

    Google Scholar 

  • De Angelo AB, Daniel FB, McMillan L, Savage RE (1989) Species and strain sensibility to the induction of peroxisome proliferation by chloroacetic acids. Toxicol Appl Pharmacol 101: 285–298

    Article  Google Scholar 

  • Elcombe CR (1985) Species differences in carcinogenicity and peroxisome proliferation due to trichloroethylene: a biochemical human hazard assessment. Arch Toxicol Suppl 8: 6–17

    PubMed  CAS  Google Scholar 

  • Elcombe CR, Rose MS, Pratt IS (1985) Biochemical, histological and ultrastructural changes in rat and mouse liver following the administration of trichloroethylene: possible relevance to species differences in hepatocarcinogenicity. Toxicol Appl Pharmacol 79: 365–376

    Article  PubMed  CAS  Google Scholar 

  • Ellin Å, Orrenius S (1975) Fatty acid hydroxylation in rat kidney cortex microsomes. Mol Cell Biochem 7: 1–11

    Google Scholar 

  • Funae Y, Imaoka S (1993) Cytochrome P450 in rodents. In: Shenkman JB, Greim H (eds) Handbook of experimental pharmacology vol 105. Springer Berlin, Heidelberg New York, pp 221–237

    Google Scholar 

  • Goldsworthy TL, Popp JA (1987) Chlorinated hydrocarbon-induced peroxisomal enzyme activity in relation to species and organ carcinogenicity. Toxicol Appl Pharmacol 88: 225–233

    Article  PubMed  CAS  Google Scholar 

  • Herren-Freund SL, Pereira MA, Khoury MD, Olson G (1987) The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver. Toxicol Appl Pharmacol 90: 183–189

    Article  PubMed  CAS  Google Scholar 

  • Hawkins JM, Jones WE, Bonner FW, Gibson GG (1987) The effect of peroxisome proliferators on microsomal, peroxisomal, and mitochondrial enzyme activities in the liver and kidney. Drug Metab Rev 18: 441–515

    Article  PubMed  CAS  Google Scholar 

  • Holme E, Greter J, Jacobson C, Lindstedt S, Nordin I, Kristiansson B, Jodal U (1989) Carnitine deficiency induced by pivampicillin and pivmecillinam therapy. Lancet 2: 469–472

    Article  PubMed  CAS  Google Scholar 

  • Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347: 645–650

    Article  PubMed  CAS  Google Scholar 

  • Klotz AV, Stogeman JJ, Walsh C (1984) An alternative 7-ethoxyresorufin O-deethylase activity assay: A continuos visible spectrophotometric method for measurement of cytochrome P-450 monooxygenase activity. Anal Biochem 140: 138–145

    Article  PubMed  CAS  Google Scholar 

  • Ko IY, Park SS, Song BJ, Patten C, Tan Y, Hah YC, Yang CS, Gelboin HV (1987) Monoclonal antibodies to ethanol-induced cytochrome P450 that metabolize aniline and nitrosamines. Cancer Res 47: 3101–3109

    PubMed  CAS  Google Scholar 

  • Krijgsheld KR, Gram TE (1984) Selective induction of renal microsomal cytochrome P450-linked monoxygenases by 1,1,-dichloroethylene in mice. Biochem Pharmacol 33: 1951–1956

    Article  PubMed  CAS  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685

    Article  PubMed  CAS  Google Scholar 

  • Longo V, Citti L, Gervasi PG (1986) Metabolism of diethylnitrosamine by nasal mucosa and hepatic microsomes from hamster and rat: species specificity of nasal mucosa. Carcinogenesis 7: 1323–1328

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275

    PubMed  CAS  Google Scholar 

  • Lundgren B, Andersson K, De Pierre JW (1992) Effects of dietary treatment with 11-dicarboxylic acids, diethylcarboxylic esters and fatty acid, on peroxisomal fatty acid β-oxidation, epoxide hydrolase and lauric acid ω-hydroxylation in mouse liver. Biochem Pharmacol 43: 785–792

    Article  PubMed  CAS  Google Scholar 

  • Melegh B, Sumegi B, Sherry AD (1993) Preferential elimination of pivalate with supplemental carnitine via formation of pivaloylcarnitine in man. Xenobiotica 23: 1255–1261

    Article  PubMed  CAS  Google Scholar 

  • Mihara K, Sato R (1972) Partial purification of NADH-cytochrome b5 reductase from rabbit liver microsomes with detergents and its proprieties. J Biochem 71: 725–735

    PubMed  CAS  Google Scholar 

  • Milton MN, Elcombe CR, Gibson GG (1990) On the mechanism of induction of microsomal cytochrome P450IVA1 and peroxisome proliferation in rat liver by clofibrate. Biochem Pharmacol 40: 2727–2732

    Article  PubMed  CAS  Google Scholar 

  • Moody DE, Gibson GG, Grant DF, Magdalou J, Sambasiva RM (1992) Peroxisome proliferators, a unique set of drug-metabolizing enzyme inducers: commentary on a symposium. Drug Metab dispos 20: 779–791

    PubMed  CAS  Google Scholar 

  • Muerhoff AS, Griffin KJ, Johnson EF (1992) The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid ω-hydroxylase, by clofibric acid. J Biol Chem 267: 19051–19053

    PubMed  CAS  Google Scholar 

  • Okita JR, Castle PJ, Okita RT (1993) Characterization of cytochromes P-450 in liver and kidney of rats treated with di-(2-ethylhexyl)phthalate. J Biochem Toxicol 8: 135–144

    Article  PubMed  CAS  Google Scholar 

  • Omura T, Sato R (1964) The carbon-monoxide binding protein of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 293: 2370–2378

    Google Scholar 

  • Parnell MJ, Koller LD, Exon JH, Arnzen JM (1986) Trichloroacetic acid effects on rat liver peroxisomes and enzyme altered foci. Environ Health Perspect 69: 70–73

    Article  Google Scholar 

  • Sharma RK, Lake BG, Makowski R, Bradshaw T, Earnshaw D, Dale JW, Gibson GG (1989) Differential induction of peroxisomal and microsomal fatty-acid-oxidising enzymes by peroxisome proliferators in rat liver and kidney. Eur J Biochem 184: 69–78

    Article  PubMed  CAS  Google Scholar 

  • Shimojo N, Ishizaki T, Imaoka S, Funae Y, Fujii S, Okuda K (1993) Changes in amounts of cytochrome P450 isozymes and levels of catalytic activities in hepatic and renal microsomes of rats with streptozocin-induced diabetes. Biochem Pharmacol 46: 621–627

    Article  PubMed  CAS  Google Scholar 

  • Towbin H, Stachelin P, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76: 4350–4354

    Article  PubMed  CAS  Google Scholar 

  • Tu YY, Yang CS (1983) High-affinity nitrosamine dealkylase system in rat liver microsomes and its induction by fasting. Cancer Res 43: 623–629

    PubMed  CAS  Google Scholar 

  • Tugwood JD, Issemann I, Anderson RG, Bundell KR, McPheat WL, Green S (1992) The mouse peroxisome proliferator activated receptor recognizes a response element in the 5′ flanking sequence of the rat acyl CoA oxidase gene. EMBO J 11: 433–439

    PubMed  CAS  Google Scholar 

  • Wickers S, Duncan CAH, White SD, Ramjit HG, Smith JL, Walker SW, Flynn H, Arison BH (1985) Carnitine and glucuronic acid conjugates of pivalic acid. Xenobiotica 15: 453–458.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zanelli, U., Puccini, P., Acerbi, D. et al. Induction of peroxisomal β-oxidation and P-450 4A-dependent activities by pivalic and trichloroacetic acid in rat liver and kidney. Arch Toxicol 70, 145–149 (1996). https://doi.org/10.1007/s002040050253

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s002040050253

Key words

Navigation