Archives of Toxicology

, Volume 79, Issue 3, pp 147–154 | Cite as

Species differences in the metabolism of di(2-ethylhexyl) phthalate (DEHP) in several organs of mice, rats, and marmosets

  • Yuki Ito
  • Hiroshi Yokota
  • Ruisheng Wang
  • Osamu Yamanoshita
  • Gaku Ichihara
  • Hailan Wang
  • Yoshimasa Kurata
  • Kenji Takagi
  • Tamie Nakajima
Toxicology and Metabolism

Abstract

To clarify species differences in the metabolism of di(2-ethylhexyl) phthalate (DEHP) we measured the activity of four DEHP-metabolizing enzymes (lipase, UDP-glucuronyltransferase (UGT), alcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH)) in several organs (the liver, lungs, kidneys, and small intestine) of mice (CD-1), rats (Sprague–Dawley), and marmosets (Callithrix jacchus). Lipase activity, measured by the rate of formation of mono(2-ethylhexyl) phthalate (MEHP) from DEHP, differed by 27- to 357-fold among species; the activity was highest in the small intestines of mice and lowest in the lungs of marmosets. This might be because of the significant differences between Vmax/Km values of lipase for DEHP among the species. UGT activity for MEHP in the liver microsomes was highest in mice, followed by rats and marmosets. These differences, however, were only marginal compared with those for lipase activity. ADH and ALDH activity also differed among species; the activity of the former in the livers of marmosets was 1.6–3.9 times greater than in those of rats or mice; the activity of the latter was higher in rats and marmosets (2–14 times) than in mice. These results were quite different from those for lipase or UGT activity. Because MEHP is considered to be the more potent ligand to peroxisome proliferator-activated receptor α involved in different toxic processes, a possibly major difference in MEHP-formation capacity could be also considered on extrapolation from rodents to humans.

Keywords

Di(2-ethylhexyl) phthalate Marmoset Metabolism Rodent Species differences 

Abbreviations

ADH

Alcohol dehydrogenase

ALDH

Aldehyde dehydrogenase

DEHP

Di(2-ethylhexyl) phthalate

2-EH

2-Ethylhexyanol

2-EHA

2-Ethylhexanoic acid

MEHP

Mono(2-ethylhexyl) phthalate

2-POET

2-Phenoxyethanol

PPARα

Peroxisome proliferator-activated receptor alpha

UGT

UDP-glucuronyl transferase

References

  1. Albro PW, Thomas RO (1973) Enzymatic hydrolysis of di(2-ethylhexyl) phthalate by lipases. Biochim Biophys Acta 360:380–390Google Scholar
  2. Albro PW, Corbett JT, Schroeder JL, Jordan S, Matthews HB (1982) Pharmacokinetics interactions with macromolecules and species differences in metabolism of DEHP. Environ Health Perspect 45:19–25PubMedGoogle Scholar
  3. Albro PW, Tondeur I, Marbury D, Jordan S, Schroeder J, Corbett JT (1983) Polar metabolites of di-(2-ethylhexyl) phthalate in the rat. Biochim Biophys Acta 18:288–292Google Scholar
  4. Albro PW (1986) Absorption, metabolism, and excretion of di(2-ethylhexyl) phthalate by rats and mice. Environ Health Perspect 65:293–298PubMedGoogle Scholar
  5. Albro PW, Lavenhar SR (1989) Metabolism of di(2-ethylhexyl) phthalate. Drug Metab Rev 21:13–34PubMedGoogle Scholar
  6. Albro PW, Chapin RE, Corbett JT, Schroeder J, Phelps JL (1989) Mono-2-ethylhexyl phthalate, a metabolite of di-(2-ethylhexyl) phthalate, causally linked to testicular atrophy in rats. Toxicol Appl Pharmacol 100:193–200CrossRefPubMedGoogle Scholar
  7. Astill B, Barber E, Lington A, Moran E, Mulholland A, Robinson E, Scheider, B (1986) Chemical industry voluntary test program for phthalate esters: health effects studies. Environ Health Perspect 65:329–336PubMedGoogle Scholar
  8. Burton SJ, Stead CV, Lowe CR (1988) Design and application of biominetic anthraquinone dyes. II. The interaction of C.I. reactive blue 2 bearing analogues terminal ring modification with horse liver alcohol dehydrogenase. J Chromatogr 455:201–206CrossRefGoogle Scholar
  9. Davis BJ, Weaver R, Gaines LJ (1994) Mono-(2-ethylhexyl) phthalate suppresses estradiol production independent of FSH-cAMP stimulation in rat granulose cells. Toxicol Appl Pharmacol 128:224–228CrossRefPubMedGoogle Scholar
  10. Gonzalez FJ (1997) Recent update on the PPAR alpha-null mouse. Biochimie 79:139–144CrossRefPubMedGoogle Scholar
  11. Hasmall HC, James NH, Macdonald N, Soames AR, Roberts RA (2000) Species differences in response to diethylhexylphthalate: suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression. Arch Toxicol 74:85–91CrossRefPubMedGoogle Scholar
  12. Huber WW, Grasl-Kraupp B, Schulte-Hermann R (1996) Hepatocarcinogenic potential of di(2-ethylhexyl) phthalate in rodents and its implications on human risk. Crit Rev Toxicol 26:365–481PubMedGoogle Scholar
  13. Japan Plasticizer Industry Association (2003) http://www.kasozai.gr.jp
  14. Kessler W, Numtip W, Grote K, Csanády GA, Chahoud I, Filser JG (2004) Blood burden of di(2-ethylhexyl) phthalate and its primary metabolite mono(2-ethylhexyl) phthalate in pregnant and nonpregnant rats and marmosets. Toxicol Appl Pharmacol 195:142–153CrossRefPubMedGoogle Scholar
  15. Klimisch HJ, Gamer AO, Hellwig J, Kauffmann W, Jackh R (1992) Di(2-ethylhexyl) phthalate: a short term repeated inhalation toxicity study including fertility assessment. Food Chem Toxicol 30:915–919CrossRefPubMedGoogle Scholar
  16. Kurata Y, Kidachi F, Yokoyama M, Toyota N, Tsuchitani M, Katoh M (1998) Subchronic toxicity of di(2-ethylhexyl) phthalate in common marmosets: lack of hepatic peroxisome proliferation, testicular atrophy, or pancreatic acinar cell hyperplasia. Toxicol Sci 42:49–56CrossRefPubMedGoogle Scholar
  17. Lake BG, Phillips JC, Linnell JC, Gangolli SD (1977) The in vitro hydrolysis of some phthalate diesters by hepatic and intestinal preparations from various species. Toxicol Appl Pharmacol 39:239–248CrossRefPubMedGoogle Scholar
  18. Maloney EK, Waxman DJ (1999) trans Activation of PPAR alpha and PPAR gamma by structurally diverse environmental chemicals. Toxicol Appl Pharmacol 161:209–218CrossRefPubMedGoogle Scholar
  19. Moody DE, Reddy JK, Lake BG, Popp JA, Reese DH (1991) Peroxisome proliferation and non-genotoxic carcinogenesis: commentary on a symposium. Fundam Appl Toxicol 6:233–248CrossRefGoogle Scholar
  20. Palmer CNA, Hsu M-H, Griffin KJ, Raucy JL, Johnson EF (1998) Peroxisome proliferator activated receptor alpha expression in human liver. Mol Pharmacol 53:14–22PubMedGoogle Scholar
  21. Pollack GM, Li RC, Ermer JC, Shen DD (1985) Effects of route of administration and repetitive dosing on the disposition kinetics of di(2-ethylhexyl) phthalate and its mono-de-esterfied metabolite in rats. Toxicol Appl Pharmacol 79:246–256CrossRefPubMedGoogle Scholar
  22. Pugh G, Isenberg JS, Kamendulis LM, Ackley DC, Clare LJ, Brown R, Lington AW, Smith JH, Klaunig JE (2000) Effects of di-isononyl phthalate, di-2-ethylhexyl phthalate, and clofibrate, in cynomolgus monkeys. Toxicol Sci 56:181–188CrossRefPubMedGoogle Scholar
  23. Rhodes C, Orton TC, Pratt IS, Batten PL, Jackson SJ, Elcombe CR (1986) Comparative pharmacokinetics and subacute toxicity of di(2-ethylhexyl)phthalate (DEHP) in rats and marmosets: extrapolation of effects in rodents to man. Environ Health Perspect 65:299–307PubMedGoogle Scholar
  24. Roberts RA, James NH, Woodyatt NJ, Macdonald N, Tugwood JD (1998) Evidence for the suppression of apoptosis by the  peroxisome  proliferator activated receptor alpha (PPAR alpha). Carcinogenesis 19:43–48CrossRefPubMedGoogle Scholar
  25. Roberts RA (1999) Peroxisome proliferators: mechanisms of adverse effects in rodents and molecular basis for species differences. Arch Toxicol 73:413–418CrossRefPubMedGoogle Scholar
  26. Sharpe RM (2001) Hormones and testis development and the possible adverse effects of environmental chemicals. Toxicol Lett 120:221–232CrossRefPubMedGoogle Scholar
  27. Sher T, Yi HF, McBride OW, Gonzalez FJ (1993) cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry 32:5598–5604PubMedGoogle Scholar
  28. Sjöberg P, Bondessen U, Kjellen L, Linquist NG, Montin G, Ploen L (1985) Kinetics of di(2-ethylhexyl) phthalate in immature and mature rats and effect on testis. Acta Pharmacol Toxicol 56:30–37Google Scholar
  29. Sjöberg P, Egestad B, Klasson-Wehler E, Gustafsson J (1991) Glucuronidation of mono(2-ethylhexyl) phthalate. Some enzyme characteristics and inhibition by bilirubin. Biochem Pharmacol 41:1493–1496CrossRefPubMedGoogle Scholar
  30. Tickner JA, Schettler T, Guidotti T, McCally M, Rossi M (2001) Health risks posed by use of di-2-ethylhexyl phthalate (DEHP) in PVC medical devices: a critical review. Am J Ind Med 39:100–111PubMedGoogle Scholar
  31. Tugwood JD, Aldridge TC, Lambe KL, Macdonald N, Woodyatt NJ (1996) PPARs: structures and function. Ann NY Acad Sci 804:252–265PubMedGoogle Scholar
  32. Tugwood JD, Holden PR, James NH, Prince RA, Roberts RA (1998) A peroxisome proliferator-activated receptor-alpha (PPARalpha) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARalpha: implications for species differences in responses to peroxisome proliferators. Arch. Toxicol 72:169–177CrossRefGoogle Scholar
  33. Wang R-S, Nakajima T, Honma T (1999) Trichloroethylene inhibits aldehyde dehydrogenase only for aliphatic aldehydes of short chains in rats. Toxicology 132:9–18CrossRefPubMedGoogle Scholar
  34. Yokota H, Iwana H, Endo M, Kobayashi T, Inoue H, Ikushiro S, Yuasa A (1999) Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP-glucuronosyltransferase, UGT2B1, in the rat liver. Biochem J 340:405–410CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Yuki Ito
    • 1
  • Hiroshi Yokota
    • 2
  • Ruisheng Wang
    • 3
  • Osamu Yamanoshita
    • 1
  • Gaku Ichihara
    • 1
  • Hailan Wang
    • 1
  • Yoshimasa Kurata
    • 4
  • Kenji Takagi
    • 5
  • Tamie Nakajima
    • 1
  1. 1.Department of Occupational and Environmental HealthNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.Department of BiochemistryRakuno Gakuen University School of Veterinary MedicineEbetsuJapan
  3. 3.National Institute of Industrial HealthKawasakiJapan
  4. 4.Department of Safety Science ResearchMitsubishi Research Institute Company LimitedKashimaJapan
  5. 5.Department of Medical TechnologyNagoya University School of Health SciencesNagoyaJapan

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