Abstract
There is evidence that the carcinogenic and teratogenic effects attributed to the plasticizer di(2-ethylhexyl)phthalate (DEHP) are due to its major metabolite mono(2-ethylhexyl)phthalate (MEHP). MEHP is also formed ex vivo by a plasma enzyme in blood products stored in polyvinyl chloride (PVC) DEHP plastic containers. People who receive large amounts of blood products, such as hemophiliacs or patients undergoing hemodialysis, cardiopulmonary bypass, or massive transfusion, are exposed to significant levels of plasticizer. In this study, the platelet was used to show that MEHP inhibits phospholipase A2 (PLA2), one of enzymes important in the release of arachidonic acid from membrane phospholipids. Arachidonate is the parent molecule for the synthesis of prostaglandins, thromboxanes, leukotrienes, and lipoxins that are made by a wide variety of cells. PLA2 was measured by the liberation of 14C-arachidonic acid from 1-stearoyl-2-[1-14C]arachidonyl-L-3-phosphatidylcholine. MEHP inhibits PLA2 activity noncompetitively in intact human platelets and lysates with a Ki of 3.7 x 10(-4) M. DEHP does not inhibit PLA2 in whole platelets. Inhibition of PLA2 by MEHP occurs at only three times the circulating level of MEHP measured in neonates undergoing exchange transfusion and 20-fold the levels experienced by patients during cardiopulmonary bypass. Therefore, infants and adult patients with multisystem failure who accumulate MEHP in their blood may be at risk for decreased platelet function.
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- Albro P. W., Thomas R. O. Enzymatic hydrolysis of di-(2-ethylhexyl) phthalate by lipases. Biochim Biophys Acta. 1973 Jun 21;306(3):380–390. doi: 10.1016/0005-2760(73)90176-8. [DOI] [PubMed] [Google Scholar]
- Ballou L. R., Cheung W. Y. Inhibition of human platelet phospholipase A2 activity by unsaturated fatty acids. Proc Natl Acad Sci U S A. 1985 Jan;82(2):371–375. doi: 10.1073/pnas.82.2.371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ballou L. R., Cheung W. Y. Marked increase of human platelet phospholipase A2 activity in vitro and demonstration of an endogenous inhibitor. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5203–5207. doi: 10.1073/pnas.80.17.5203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cole R. S., Tocchi M., Wye E., Villeneuve D. C., Rock G. Contamination of commercial blood products by di-2-ethylhexyl phthalate and mono-2-ethylhexyl phthalate. Vox Sang. 1981 May;40(5):317–322. doi: 10.1111/j.1423-0410.1981.tb00715.x. [DOI] [PubMed] [Google Scholar]
- Gangolli S. D. Testicular effects of phthalate esters. Environ Health Perspect. 1982 Nov;45:77–84. doi: 10.1289/ehp.824577. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gray T. J., Lake B. G., Beamand J. A., Foster J. R., Gangolli S. D. Peroxisomal effects of phthalate esters in primary cultures of rat hepatocytes. Toxicology. 1983 Sep;28(1-2):167–179. doi: 10.1016/0300-483x(83)90115-4. [DOI] [PubMed] [Google Scholar]
- Gray T. J., Rowland I. R., Foster P. M., Gangolli S. D. Species differences in the testicular toxicity of phthalate esters. Toxicol Lett. 1982 Apr;11(1-2):141–147. doi: 10.1016/0378-4274(82)90119-9. [DOI] [PubMed] [Google Scholar]
- Kashuk J. L., Moore E. E., Millikan J. S., Moore J. B. Major abdominal vascular trauma--a unified approach. J Trauma. 1982 Aug;22(8):672–679. doi: 10.1097/00005373-198208000-00004. [DOI] [PubMed] [Google Scholar]
- Kluwe W. M., Haseman J. K., Douglas J. F., Huff J. E. The carcinogenicity of dietary di(2-ethylhexyl) phthalate (DEHP) in Fischer 344 rats and B6C3F1 mice. J Toxicol Environ Health. 1982 Oct-Nov;10(4-5):797–815. doi: 10.1080/15287398209530296. [DOI] [PubMed] [Google Scholar]
- Lagarde M., Menashi S., Crawford N. Localisation of phospholipase A2 and diglyceride lipase activities in human platelet intracellular membranes. FEBS Lett. 1981 Feb 9;124(1):23–26. doi: 10.1016/0014-5793(81)80045-2. [DOI] [PubMed] [Google Scholar]
- Lutz W. K. Investigation of the potential for binding of di(2-ethylhexyl) phthalate (DEHP) to rat liver DNA in vivo. Environ Health Perspect. 1986 Mar;65:267–269. doi: 10.1289/ehp.8665267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mitchell A. M., Lhuguenot J. C., Bridges J. W., Elcombe C. R. Identification of the proximate peroxisome proliferator(s) derived from di(2-ethylhexyl) phthalate. Toxicol Appl Pharmacol. 1985 Aug;80(1):23–32. doi: 10.1016/0041-008x(85)90097-3. [DOI] [PubMed] [Google Scholar]
- Pollack G. M., Buchanan J. F., Slaughter R. L., Kohli R. K., Shen D. D. Circulating concentrations of di(2-ethylhexyl) phthalate and its de-esterified phthalic acid products following plasticizer exposure in patients receiving hemodialysis. Toxicol Appl Pharmacol. 1985 Jun 30;79(2):257–267. doi: 10.1016/0041-008x(85)90347-3. [DOI] [PubMed] [Google Scholar]
- Reddy J. K., Lalwai N. D. Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit Rev Toxicol. 1983;12(1):1–58. doi: 10.3109/10408448309029317. [DOI] [PubMed] [Google Scholar]
- Rock G. A., Farrah G., Rozon G., Smiley R. K., Cole R., Villeneuve D., Tittley P. Analysis of contaminants in factor VIII preparations administered to patients with hemophilia. Can Med Assoc J. 1983 Feb 15;128(4):403–408. [PMC free article] [PubMed] [Google Scholar]
- Rock G., Labow R. S., Franklin C., Burnett R., Tocchi M. Hypotension and cardiac arrest in rats after infusion of mono(2-ethylhexyl) phthalate (MEHP), a contaminant of stored blood. N Engl J Med. 1987 May 7;316(19):1218–1219. doi: 10.1056/NEJM198705073161915. [DOI] [PubMed] [Google Scholar]
- Rock G., Secours V. E., Franklin C. A., Chu I., Villeneuve D. C. The accumulation of mono-2-ethylhexylphthalate (MEHP) during storage of whole blood and plasma. Transfusion. 1978 Sep-Oct;18(5):553–558. doi: 10.1046/j.1537-2995.1978.18579036383.x. [DOI] [PubMed] [Google Scholar]
- Tavares I. A., Bennett A., Gaffen J. D., Morris H. R., Taylor G. W. The biological activities of phthalate esters on rat gastric muscle. Eur J Pharmacol. 1984 Nov 13;106(2):449–452. doi: 10.1016/0014-2999(84)90738-6. [DOI] [PubMed] [Google Scholar]