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. 1982 Nov;45:27–34. doi: 10.1289/ehp.824527

Hepatic effects of phthalate esters.

P K Seth
PMCID: PMC1568985  PMID: 6754361

Abstract

Di(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer and microchemical environmental pollutant, produces subtle changes in hepatic function as judged by increase in liver weight and morphological and biochemical alterations. It can modify the biological response of drugs and other xenobiotics. Such interactions appear to occur at the pharmacokinetic phase, as DEHP was found to alter the activity of microsomal drug-metabolizing enzymes and ethanol metabolism. DEHP produced a time- and route-dependent effect on the hepatic cytochrome P-450 contents and activity of aminopyrine N-demethylase, aniline hydroxylase, alcohol dehydrogenase and high and low Km aldehyde dehydrogenases when given orally or intraperitoneally. Under in vitro conditions, DEHP produced no effect on the activity of aminopyrine N-demethylase or aniline hydroxylase, while mono(2-ethylhexyl) phthalate (MEHP) and 2-ethylhexanol (2-EH) significantly inhibited their activity at concentrations ranging from 2.5 to 15.0 mM. Activity of aminopyrine N-demethylase and aniline hydroxylase was also inhibited by dimethyl phthalate (DMP) and dibutyl phthalate (DBP) after a single oral administration. In view of the possibility of the human exposure to phthalates and other xenobiotics simultaneously, these observations are of great significance.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albro P. W., Thomas R., Fishbein L. Metabolism of diethylhexyl phthalate by rats. Isolation and characterization of the urinary metabolites. J Chromatogr. 1973 Feb 28;76(2):321–330. doi: 10.1016/s0021-9673(01)96915-8. [DOI] [PubMed] [Google Scholar]
  2. Bell F. P., Nazir D. J. Effect of dietary di-2-ethylhexyl phthalate on lipid biosynthesis in selected tissues from the rat, in vitro. Lipids. 1976 Mar;11(3):216–221. doi: 10.1007/BF02532860. [DOI] [PubMed] [Google Scholar]
  3. Bell F. P., Patt C. S., Brundage B., Gillies P. J., Phillips W. A. Studies on lipid biosynthesis and cholesterol content of liver and serum lipoproteins in rats fed various phthalate esters. Lipids. 1978 Jan;13(1):66–74. doi: 10.1007/BF02533369. [DOI] [PubMed] [Google Scholar]
  4. CARPENTER C. P., WEIL C. S., SMYTH H. F., Jr Chronic oral toxicity of di-(2-ethylhexyl) phthalate of rats, guinea pigs, and dogs. AMA Arch Ind Hyg Occup Med. 1953 Sep;8(3):219–226. [PubMed] [Google Scholar]
  5. Calley D., Autian J., Guess W. L. Toxicology of a series of phthalate esters. J Pharm Sci. 1966 Feb;55(2):158–162. doi: 10.1002/jps.2600550206. [DOI] [PubMed] [Google Scholar]
  6. Carter J. E., Roll D. B., Petersen R. V. The in vitro hydrolysis of di-(2-ethylhexyl) phthalate by rat tissues. Drug Metab Dispos. 1974 Jul-Aug;2(4):341–344. [PubMed] [Google Scholar]
  7. Daniel J. W., Bratt H. The absorption, metabolism and tissue distribution of di(2-ethylhexyl)phthalate in rats. Toxicology. 1974 Mar;2(1):51–65. doi: 10.1016/0300-483x(74)90042-0. [DOI] [PubMed] [Google Scholar]
  8. Gray T. J., Butterworth K. R., Gaunt I. F., Grasso G. P., Gangolli S. D. Short-term toxicity study of di-(2-ethylhexyl) phthalate in rats. Food Cosmet Toxicol. 1977 Oct;15(5):389–399. doi: 10.1016/s0015-6264(77)80003-5. [DOI] [PubMed] [Google Scholar]
  9. Inouye B., Ogino Y., Ishida T., Ogata M., Utsumi K. Effects of phthalate esters on mitochondrial oxidative phosphorylation in the rat. Toxicol Appl Pharmacol. 1978 Jan;43(1):189–198. doi: 10.1016/s0041-008x(78)80043-x. [DOI] [PubMed] [Google Scholar]
  10. Jacobson M. S., Kevy S. V., Grand R. J. Effects of a plasticizer leached from polyvinyl chloride on the subhuman primate: a consequence of chronic transfusion therapy. J Lab Clin Med. 1977 May;89(5):1066–1079. [PubMed] [Google Scholar]
  11. Kasuya M. Toxicity of phthalate esters to nervous tissue in culture. Bull Environ Contam Toxicol. 1974 Aug;12(2):167–172. doi: 10.1007/BF01684955. [DOI] [PubMed] [Google Scholar]
  12. Lake B. G., Brantom P. G., Gangolli S. D., Butterworth K. R., Grasso P. Studies on the effects of orally administered Di-(2-ethylhexyl) phthalate in the ferret. Toxicology. 1976 Nov-Dec;6(3):341–356. doi: 10.1016/0300-483x(76)90038-x. [DOI] [PubMed] [Google Scholar]
  13. Lake B. G., Gangolli S. D., Grasso P., Lloyd A. G. Studies on the hepatic effects of orally administered di-)2-ethylhexyl) phthalate in the rat. Toxicol Appl Pharmacol. 1975 May;32(2):355–367. doi: 10.1016/0041-008x(75)90226-4. [DOI] [PubMed] [Google Scholar]
  14. Lake B. G., Phillips J. C., Linnell J. C., Gangolli S. D. The in vitro hydrolysis of some phthalate diesters by hepatic and intestinal preparations from various species. Toxicol Appl Pharmacol. 1977 Feb;39(2):239–248. doi: 10.1016/0041-008x(77)90157-0. [DOI] [PubMed] [Google Scholar]
  15. Lawrence W. H., Malik M., Turner J. E., Singh A. R., Autian J. A toxicological investigation of some acute, short-term, and chronic effects of administering di-2-ethylhexyl phthalate (DEHP) and other phthalate esters. Environ Res. 1975 Feb;9(1):1–11. doi: 10.1016/0013-9351(75)90043-2. [DOI] [PubMed] [Google Scholar]
  16. Lawrence W. H., Tuell S. F. Phthalate esters: the question of safety--an update. Clin Toxicol. 1979;15(4):447–466. doi: 10.3109/15563657908989899. [DOI] [PubMed] [Google Scholar]
  17. Mushtaq M., Srivastava S. P., Seth P. K. Effect of di-2-ethylhexyl phthalate (DEHP) on glycogen metabolism in rat liver. Toxicology. 1980;16(2):153–161. doi: 10.1016/0300-483x(80)90045-1. [DOI] [PubMed] [Google Scholar]
  18. Nazir D. J., Alcaraz A. P., Bierl B. A., Beroza M., Nair P. P. Isolation, identification, and specific localization of di-2-ethylhexyl phthalate in bovine heart muscle mitochondria. Biochemistry. 1971 Nov;10(23):4228–4232. doi: 10.1021/bi00799a012. [DOI] [PubMed] [Google Scholar]
  19. Nikonorow M., Mazur H., Piekacz H. Effect of orally administered plasticizers and polyvinyl chloride stabilizers in the rat. Toxicol Appl Pharmacol. 1973 Oct;26(2):253–259. doi: 10.1016/0041-008x(73)90259-7. [DOI] [PubMed] [Google Scholar]
  20. Ohyama T. Effects of phthalate esters on the respiration of rat liver mitochondria. J Biochem. 1976 Jan;79(1):153–158. doi: 10.1093/oxfordjournals.jbchem.a131042. [DOI] [PubMed] [Google Scholar]
  21. Omori Y. Recent progress in safety evaluation studies on plasticizers and plastics and their controlled use in Japan. Environ Health Perspect. 1976 Oct;17:203–209. doi: 10.1289/ehp.7617203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Osumi T., Hashimoto T. Enhancement of fatty acyl-CoA oxidizing activity in rat liver peroxisomes by di-(i-ethylhexyl)phthalate. J Biochem. 1978 May;83(5):1361–1365. doi: 10.1093/oxfordjournals.jbchem.a132044. [DOI] [PubMed] [Google Scholar]
  23. Peck C. C., Odom D. G., Friedman H. I., Albro P. W., Hass J. R., Brady J. T., Jess D. A. Di-2-ethylhexyl phthalate (DEHP) and mono-2-ethylhexyl phthalate (MEHP) accumulation in whole blood and red cell concentrates. Transfusion. 1979 Mar-Apr;19(2):137–146. doi: 10.1046/j.1537-2995.1979.19279160282.x. [DOI] [PubMed] [Google Scholar]
  24. Reddy J. K., Moody D. E., Azarnoff D. L., Rao M. S. Di-(2-ethylhexyl)phthalate: an industrial plasticizer induces hypolipidemia and enhances hepatic catalase and carnitine acetyltransferase activities in rat and mice. Life Sci. 1976 May 1;18(9):941–945. doi: 10.1016/0024-3205(76)90412-4. [DOI] [PubMed] [Google Scholar]
  25. Rubin R. J., Jaeger R. J. Some pharmacologic and toxicologic effects of di-2-ethylhexyl phthalate (DEHP) and other plasticizers. Environ Health Perspect. 1973 Jan;3:53–59. doi: 10.1289/ehp.730353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sakurai T., Miyazawa S., Hashimoto T. Effects of di-(2-ethylhexyl)phthalate administration on carbohydrate and fatty acid metabolism in rat liver. J Biochem. 1978 Jan;83(1):313–320. doi: 10.1093/oxfordjournals.jbchem.a131906. [DOI] [PubMed] [Google Scholar]
  27. Seth P. K., Srivastava S. P., Agarwal D. K., Chandra S. V. Effect of di-2-ethylhexyl phthalate (DEHP) on rat gonads. Environ Res. 1976 Oct;12(2):131–138. doi: 10.1016/0013-9351(76)90015-3. [DOI] [PubMed] [Google Scholar]
  28. Seth P. K., Srivastava S. P., Agarwal D. K., Mushtaq M. Interaction of di-(2-ethylhexyl)-phthalate (DEHP) with pentabarbitone and methaqualone. Bull Environ Contam Toxicol. 1977 Jun;17(6):727–732. doi: 10.1007/BF01685961. [DOI] [PubMed] [Google Scholar]
  29. Seth P. K., Srivastava S. P., Mushtaq M., Agarwal D. K., Chandra S. V. Effect of di-(2-ethylhexyl) phthalate on rat liver injured by chronic carbon tetrachloride treatment. Acta Pharmacol Toxicol (Copenh) 1979 Mar;44(3):161–167. doi: 10.1111/j.1600-0773.1979.tb02312.x. [DOI] [PubMed] [Google Scholar]
  30. Singh A. R., Lawrence W. H., Autian J. Teratogenicity of phthalate esters in rats. J Pharm Sci. 1972 Jan;61(1):51–55. doi: 10.1002/jps.2600610107. [DOI] [PubMed] [Google Scholar]
  31. Srivastava S. P., Agarwal D. K., Mushtaq M., Seth P. K. Effect of Di-(2-ethylhexyl) phthalate (DEHP) on chemical constituents and enzymatic activity of rat liver. Toxicology. 1978 Nov;11(3):271–275. doi: 10.1016/s0300-483x(78)91639-6. [DOI] [PubMed] [Google Scholar]
  32. Srivastava S. P., Agarwal D. K., Seth P. K. Effect of di-2-ethylhexyl phthalate on the activity of succinic dehydrogenase and adenosine triphosphatase of some vital organs of rat. Toxicology. 1977 Apr;7(2):163–168. doi: 10.1016/0300-483x(77)90061-0. [DOI] [PubMed] [Google Scholar]
  33. Srivastava S. P., Seth P. K., Agarwal D. K. Biochemical effects of di-2-ethylhexyl phthalate. Environ Physiol Biochem. 1975;5(3):178–183. [PubMed] [Google Scholar]
  34. Stein M. S., Caasi P. I., Nair P. P. Influence of dietary fat and di-2-ethylhexyl phthalate on tissue lipids in rats. J Nutr. 1974 Feb;104(2):187–191. doi: 10.1093/jn/104.2.187. [DOI] [PubMed] [Google Scholar]
  35. Takahashi T. Biochemical studies on phthalic esters--II. Effects of phthalic esters on mitochondrial respiration of rat liver. Biochem Pharmacol. 1977 Jan 1;26(1):19–24. doi: 10.1016/0006-2952(77)90124-1. [DOI] [PubMed] [Google Scholar]
  36. Tanaka A., Adachi T., Takahashi T., Yamaha T. Biochemical studies on phthalic esters I. Elimination, distribution and metabolism of di-(2-ethylhexyl)phthalate in rats. Toxicology. 1975 May;4(2):253–264. doi: 10.1016/0300-483x(75)90105-5. [DOI] [PubMed] [Google Scholar]
  37. Thomas J. A., Darby T. D., Wallin R. F., Garvin P. J., Martis L. A review of the biological effects of di-(2-ethylhexyl) phthalate. Toxicol Appl Pharmacol. 1978 Jul;45(1):1–27. doi: 10.1016/0041-008x(78)90024-8. [DOI] [PubMed] [Google Scholar]
  38. Tomita I., Nakamura Y., Yagi Y. Phthalic acid esters in various foodstuffs and biological materials. Ecotoxicol Environ Saf. 1977 Sep;1(2):275–287. doi: 10.1016/0147-6513(77)90043-4. [DOI] [PubMed] [Google Scholar]
  39. Williams D. T., Blanchfield B. J. Retention, excretion and metabolism of di-(2-ethylhexyl) phthalate administered orally to the rat. Bull Environ Contam Toxicol. 1974 Apr;11(4):371–378. doi: 10.1007/BF01684945. [DOI] [PubMed] [Google Scholar]
  40. Yanagita T., Kobayashi K., Enomoto N. Accumulation of hepatic phospholipids in rats fed di-2-ethylhexyl phthalate. Biochem Pharmacol. 1978;27(19):2283–2288. doi: 10.1016/0006-2952(78)90132-6. [DOI] [PubMed] [Google Scholar]
  41. Yanagita T., Kuzuhara S., Enomoto N., Shimada T., Sugano M. Effects of DI-(2-ethylhexyl) phthalate on the content and composition of hepatic mitochondrial and microsomal phospholipids in the rat. Biochem Pharmacol. 1979 Oct 15;28(20):3115–3121. doi: 10.1016/0006-2952(79)90621-x. [DOI] [PubMed] [Google Scholar]

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