The Metabolism of Mono-(2-Ethylhexyl) Phthalate (Mehp) and Liver Peroxisome Proliferation in the Hamster

Abstract

This study has investigated the in vivo metabolism of mono-(2-ethylhexyl) phthalate (MEHP), the initial metabolite of di-(2-ethylhexyl) phthalate in mammals, and the hepatic peroxisome proliferation induced by this compound following multiple oral administration to hamsters. Hamsters received [¹⁴C]-MEHP, by gavage, at doses of 50 and 500 mg/kg body wt on each of three consecutive days. Urine was collected every 24 hours and metabolite profiles were determined using capillary gas-chromatography. Multiple high doses of MEHP (500 mg/kg) induced a change in the relative proportions of metabolites produced. As previously reported for the rat, metabolites derived from sequential ω-following by β-oxidation were increased. This increase was correlated with a parallel 3-fold increase in peroxisomal β-oxidation-a marker for peroxisome proliferation. Hamsters were less responsive than rats to peroxisome proliferation elicited by MEHP. In contrast to the rat, a large proportion of hamster ω-1 oxidation products of MEHP (metabolites 6 and 9, mono (2-ethylhexyl-5-oxohexyl) phthalate and mono (2-ethyl 5-hydroxyhexyl) phthalate, respectively) were found as their glucuronide conjugates. This metabolic species difference may relate to differences in sensitivity to MEHP as a peroxisome proliferator. The relationship between metabolite conjugation, peroxisome proliferation and production of ω-oxidation metabolites is discussed.

Keywords

MEHP peroxisome proliferation.

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References

Albro, P.W. , Thomas, R.O. and Fishbein, L. (1973). Metabolism of diethylhexyl phthalate by rats. Isolation and characterization of the urinary metabolites. J. Chromat. 76:321-330.

Albro, P.W. , Hass, J.R. , Peck, C.C. , Odam, D.G. , Corbett, J.T. , Bailey, J.F. , Blatt, H.E. and Barrett, B.B. (1981). Identification of the metabolites of di-(2-ethylhexyl) phthalate in urine from the African green monkey. Drug Metab. Dispos. 9:223-225.

Albro, P.W. , Jordan, S.T. , Schroder, J.L. and Corbett, J.T. (1982). Chromatographic separation and quantitative determination of the metabolites of di-(2-ethylhexyl) phtalate from urine of laboratory animals. J. Chromatogr. 244:65-79.

Ashby, J. , De Serres, F.J. , Draper, M. , Ishidate, M. , Margolin, B.H. , Matter, B. and Shelby, M.D. (1985). Overview and conclusions of the IPCS collaborative study on in vitro assay systems. Prog. Mutat. Res. 5:117-174.

Bronfman, M. , Inestrosa, N.C. and Leighton, F. (1979). Fatty acid oxidation by human liver peroxisomes . Biochem. Biophys. Res. Commun. 88:1030-1036.

Chu, I. , Villeneuve, D.C. , Secours, V. , Franklin, C. , Rock, G. and Viau, A. (1978). Metabolism and tissue distribution of mono-2-ethylhexyl phthalate in the rat. Drug Metab. Dispos. 6:146-149.

Daniel, J.W. and Bratt, H. (1974). The absorption, metabolism and tissue distribution of di-(2-ethylhexyl) phthalate in rats. Toxicology 2:51-56.

Harvan, D.J. , Hass, J.R. , Albro, P.W. and Friesen, M.D. (1980). Mass spectrometry of di-(2-ethylhexyl) phthalate metabolites. Biomed. Mass Spectrom. 7:242-246.

Keglevic, D. , Pradvic, N. and Tomasi, J. (1968). Glucuronic esters. Part IV. Synthesis of 1-0-Acyl-D-glucopyranuronic acids via Benzyl 1-0-Acyl-2, 3,4-tri-0-benzyl-D-glucopyranuronates. J. Chem. Soc., C, 511≥517.

10.

Lake, B.G. , Gray, T.J.B. , Foster, J.R. , Stubberfield, C.R. and Gangolli, S.D. (1984). Comparative studies on di-(2-ethylhexyl) phthalate induced hepatic peroxisome proliferation in the rat and hamster. Toxicol. Appl. Pharmacol. 72:46-60.

11.

Lazarow, P.B. (1981). Assay of peroxisomal β-oxidation of fatty acids. In: Methods in Enzymology ( J.M. Lowenstein , ed.), vol. 72, Lipids Part D, pp. 315-317, Academic Press, New York.

12.

Lhuguenot, J.C. , Mitchell, A.M. , Milner, G. , Lock, E.A. and Elcombe, C.R. (1985). The metabolism of di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate in rats: In vivo and in vitro dose and time dependency of metabolism. Toxicol. Appl. Pharmacol. 80:11-22.

13.

Lowry, O.H. , Rosenbrough, N.J. , Farr, A.L. and Randall, R.J. (1951). Protein measurements. J. Biol. Chem. 193 :265-275.

14.

Mitchell, A.M. , Lhuguenot, J.C. , Bridges, J.W. and Elcombe, C.R. (1985). Identification of the proximate peroxisome proliferator(s) derived from di-(2-ethylhexyl) phthalate. Toxicol. Appl. Pharmacol . 80:23-32.

15.

Moody, D.E. and Reddy, J.K. (1978). Hepatic peroxisome (microbody) proliferation in rats fed plasticizers and related compounds. Toxicol. Appl. Pharmacol. 45:497-504.

16.

National Toxicology Program. (1982). Carcinogenesis bioassay of di-(2-ethylhexyl) phthalate (CAS n° 117-81-7) in F344 rats and B6C3F1 mice (Feed study). (Technical report series n° 217). (NIH publ. n° 82-1773, Research Triangle Park, NC).

17.

Orton, T.C. , Adam, H.K. , Bentley, M. , Holloway, B. and Tucker, M.J. (1984). Clobuzarit: species differences in the morphological and biochemical response of the liver following chronic administration. Toxicol. Appl. Pharmacol. 73:138-151.

18.

Osumi, T. and Hashimoto, T. (1979). Subcellular distribution of the enzymes of the fatty acyl CoA β-oxidation system and their induction by di-(2-ethylhexyl) phthalate in rat liver. J. Biochem. (Tokyo) 85:131-139.

19.

Reddy, J.K. and Lalwani, N.D. (1984). Carcinogenesis by hepatic peroxisome proliferators : Evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit. Rev. Toxicol. 12:1-58.

20.

Rhodes, C. , Orton, T.C. , Pratt, I.S. , Batten, P.L. , Bratt, H. , Jackson, S.J. and Elcombe, C.R. (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. 65:299-308.

21.

Schulz, C.O. and Rubin, R.J. (1973). Distribution, metabolism and excretion of di-(2-ethylhexyl) phthalate in the rat. Environ. Health Perspect. 3:123-129.

22.

Tanaka, A. , Adachi, T. , Takahashi, T. and Yamaha, T. (1975). Biochemical studies on phthalic esters. I. Elimination, distribution and metabolism of di-(2-ethylhexyl) phthalate in rats. Toxicology 4:253-264.

23.

Thomas, J.A. and Northrup, S.J. (1982). Toxicity and metabolism of monoethylhexyl phthalate and diethylhexyl phthalate: a survey of recent literature. J. Toxicol. Environ. Hlth. 9:141-152.

24.

Williams, D.T. and Blanchfield, B.J. (1974). Retention, excretion and metabolism of di-(2-ethylhexyl) phthalate administered orally to the rat. Bull. Environ. Contam. Toxicol. 11:371-387.