Archives of Toxicology

, Volume 50, Issue 1, pp 1–10 | Cite as

Phthalate esters I: effects on cytochrome P-450 mediated metabolism in rat liver and lung, serum enzymatic activities and serum protein levels

  • Frode Walseth
  • Rune Toftgård
  • Odd G. Nilsen
Original Investigations


Dimethylphthalate (DMP), dibutylphthalate (DBP) and di(2-ethylhexyl)phthalate (DEHP) were given i.p. (3.8 mM/kg) to Sprague Dawley rats for 5 days. DBP increased significantly the liver concentration of cytochrome P-450, but decreased the lung concentration by about 40%. DBP decreased the lung concentration of cytochrome b5 and NADPH-cytochrome-c-reductase activity by about 30%. Only minor effects were seen after treatment with DMP and DEHP. The direction of B(a)P metabolism was changed and the formation of 2- and 3-hexanol metabolites were increased in liver microsomes after DBP treatment. All phthalate esters decreased the lung metabolism of B(a)P. The cytochrome P-450 enzyme system in the lung was ten times more effective than that in the liver as far as metabolism of n-hexane was concerned. Only minor effects were observed in serum enzyme activities, but a significant decrease in the serum level of albumin was observed after treatment with DBP. No relationship was found between the carbon chain length of the investigated chemicals and effects on microsomal enzymatic activities.

Key words

Phthalate esters Liver Lung Blood Rat Enzymatic activities 


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  1. Aitio A, Parkki M (1978) Effect of phthalate esters on drug metabolizing enzyme activities in rat liver. Arch Int Pharmacodyn 235: 187–195Google Scholar
  2. Albro PW, Thomas RO (1973) Enzymatic hydrolysis of di-(2-ethylhexyl)phthalate by lipases. Biochem Biophys Acta 36: 380–390Google Scholar
  3. Daniel JW (1978) Toxicity and metabolism of phthalate esters. Clin Toxicol 13: 257–268Google Scholar
  4. Dvoskin YG, Rakhmania NA, Dem'yanko FV, Menshikova TA, Erofeeva LF, Lashkina AV (1969) Hygienic assessment of “pavinol”. Gig Sanit 34: 8–12Google Scholar
  5. Gornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reaction. J Biol Chem 177: 715–766Google Scholar
  6. Ingelman-Sundberg M, Johansson I, Brunstrøm A, Ekstrøm G, Haaparanta T, Rydstrøm J (1980) The importance of cytochrome b5 and negatively charged phospholipids in electron transport to different types of liver microsomal cytochrome P-450 in reconstituted phospholipid vesicles. In: Gustafsson J-Å, Carlstedt-Duke J, Mode A, Rafter J (eds) Developments in biochemistry, vol 13. Elsevier/North-Holland, Amsterdam, p 299Google Scholar
  7. Jaeger RJ, Rubin RJ (1973) Extraction, localization, and metabolism of di-2-ethylhexyl phthalate from PVC plastic medical devices. Environ Health Perspect 3: 95–102Google Scholar
  8. Johannesen KAM, DePierre JW (1978) Measurement of cytochrome P-450 in the presence of large amounts of contaminating hemoglobin and methemoglobin. Anal Biochem 86: 725–732Google Scholar
  9. Johannesen K, DePierre JW, Bergstrand A, Dallner G, Ernster L (1977) Preparation and characterization of total, rough and smooth microsomes from the lung of control and methylcholanthrene-treated rats. Biochim Biophys Acta 496: 115–135Google Scholar
  10. Laemmli MK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T 4. Nature 227: 680–685Google Scholar
  11. Lake BG, Gangolli SD, Grasso P, Lloyd AG (1975) Studies on the hepatic effects of orally administered di-(2-ethylhexyl)phthalate in the rat. Toxicol Appl Pharmacol 32: 355–367Google Scholar
  12. Lake BG, Phillips JC, Linell JC, Gangolli SD (1977) The in vitro hydrolysis of some phthalate diesters by hepatic and intestinal preparations from various species. Toxicol Appl Pharmacol 39: 239–248Google Scholar
  13. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193: 265–275Google Scholar
  14. Mayer FL, Stalling DL, Johnson JL (1972) Phthalate esters as environmental contaminants. Nature 238: 411–413Google Scholar
  15. Mez J, Coffin DE, Campbell DS (1974) Di-n-butyl- and di-2-ethylhexyl phthalate in human adipose tissue. Bull Environ Contam Toxicol 12: 721–725Google Scholar
  16. Nazir DR, Alcaraz AP, Bierl BA, Beroza M, Nair PP (1971) Isolation, identification, and specific localization of di-2-ethylhexyl phthalate in bovine heart muscle mitochondria. Biochemistry 10: 4228–4232Google Scholar
  17. Nilsen OG, Toftgård R, Eng L, Gustafsson J-Å (1981) Regio-selectivity of purified forms of rabbit liver microsomal cytochrome P-450 in the metabolism of benzo(a)pyrene, n-hexane and 7-ethoxyresorufin. Acta Pharmacol Toxicol 48: 369–376Google Scholar
  18. Noshiro M, Ruf HH, Ullrich V (1980) The role of NADPH-cytochrome P-450 reductase and cytochrome b5 in the transfer of electrons from NADPH and NADH to cytochrome P-450. In: Gustafsson J-Å, Carlstedt-Duke J, Mode A, Rafter J (eds) Developments in biochemistry, vol 13. Elsevier/North-Holland, Amsterdam, p 351Google Scholar
  19. Ohyama T (1977) Effects of phthalate esters on glucose 6-phosphate dehydrogenase and other enzymes in vitro. Toxicol Appl Pharmacol 40: 355–364Google Scholar
  20. Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 239: 2370–2378Google Scholar
  21. Patel JM (1979) The destruction of pulmonary and hepatic cytochrome P-450 by phthalaldehyde. Toxicol Appl Pharmacol 48: 337–342Google Scholar
  22. Pinnel AE, Northam BE (1978) New automated dye-binding method for serum albumin determination with bromcresol purple. Clin Chem 24: 80–86Google Scholar
  23. Srivastava SP, Agarwal DK, Mushtaq M, Seth PK (1978) Effect of di-(2-ethylhexyl)-phthalate (DEHP) on chemical constituents and enzymatic activity of rat liver. Toxicology 11: 271–275Google Scholar
  24. The Committee on Enzymes of the Scandinavian Society for Clinical Chemistry and Clinical Physiology (1974) Recommended methods for the determination of four enzymes in blood. Scand J Clin Lab Invest 33: 287–291Google Scholar
  25. Toftgård R, Nilsen OG, Ingelman-Sundberg M, Gustafsson J-Å (1980) Correlation between changes in enzymatic activities and induction of different forms of rat liver microsomal cytochrome P-450 after phenobarbital-, 3-methylcholanthrene- and 16α-cyanopregnenolone treatment. Acta Pharmacol Toxicol 46: 353–361Google Scholar
  26. Vatsis KP, Gurka DP, Hollenberg PF (1980) Involvement of cytochrome b5 in the NADPH-dependant regioselective hydroxylation of n-methylcarbazole by cytochromes P-450LM2 and P-450LM4 in a reconstituted liver microsomal enzyme system. In: Gustafsson J-Å, Carlstedt-Duke J, Mode A, Rafter J (eds) Developments in biochemistry, vol 13, Elsevier/North-Holland, Amsterdam, p 347Google Scholar
  27. Williams CH, Kamin H (1962) Microsomal triphosphopyridine nucleotide-cytochrome c reductase of liver. J Biol Chem 237: 587–595Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • Frode Walseth
    • 1
  • Rune Toftgård
    • 2
  • Odd G. Nilsen
    • 1
  1. 1.Department of Pharmacology and ToxicologySchool of Medicine, University of Trondheim, Regional HospitalTrondheimNorway
  2. 2.Department of Medical Nutrition and Department of PharmacologyKarolinska InstitutetStockholmSweden

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