The diphenyl-ether herbicides exert their phytotoxic activity by preventing chlorophyll formation in plants as a result of inhibition of protoporphyrinogen oxidase. This enzyme is the last step of the common pathway for chlorophyll and haem biosynthesis.
The aim of this work is to determine whether herbicide inhibitors of plant protoporphyrinogen oxidase could act on the human protoporphyrinogen oxidase involved in haemoglobin synthesis and cause heamatologic diseases. Human erythroblastic progenitors (BFU-E/CFU-E: Burst Forming Unit-Erythroid and Colony Forming Unit-Ery throid) were exposed to oxyfluorfen, a diphenyl-ether herbicide in the presence of erythropoietin, and the haematoxicity evaluated in vitro by scoring the develop ment of BFU-E/CFU-E colonies after 7 and 14 days of culture. The toxic effect on differentiation has been evaluated using four criteria: morphology, total protein, total porphyrin, and haemoglobin content. The study of BFU-E/CFU-E proliferation and differentia tion showed a cytotoxic effect of oxyfluorfen only at very high concentrations. In contrast, haemoglobin synthesis can be inhibited by concentration of oxyfluorfen (10-4 M) that have no adverse effect on cellular proliferation.
Nordmann Y., Grandchamp B.Anomalies héréditaires de la biosynthèse de l'hème: les porphyries In: Hematologie. Dreyfus B (ed.), Flammarion Médecine-Sciences, Paris, 1992; pp. 425-446.
2.
Del Battle AMLead intoxication and acute porphyria: development and positive experience in their therapy In: Porphyrins and Porphyrias. Nordmann Y (ed.), colloque Inserm/John. Libbey Eurotext, London-Paris , 1986; 134: pp. 189- 200.
3.
Sassa S., Anderson KE, Kappa A.Uroporphyrinogen decarboxylase: genetic defects and inhibition by environmental chemicals In: Porphyrins and Porphyrias. Nordmann Y (ed.), colloque Inserm/John. Libbey Eurotext, London-Paris, 1986; 134 : pp. 45- 53.
4.
Matringe M., Camadro JM, Labbe P., Scalla R.Protoporphyrinogen oxidase inhibition by three peroxidizing herbicides: oxadiazon, LS 82-556 and M&B 39279FEBS Letters , 1989; 245: 35-38.
5.
Matringe M., Camadro JM, Labbe P., Scalla R.Protoporphyrinogen oxidase as a molecular target for diphenyl ether herbicidesBiochemical Journal1989 ; 260: 231-235.
6.
Camadro JM, Matringe M., Scalla R., Labbe P.Kinetic studies on protoporphyrinogen oxidase inhibition by diphenyl ether herbicidesBiochemical Journal1991; 277: 17-21.
7.
Boorman GA, Luster MI, Dean JH, Campbell MLAssessment of myelotoxicity caused by environmental chemicalsEnvironmental Health Perspectives1982; 43: 129 - 135.
8.
Naughton BA, Sibanda D., Azar L., San Roman J.Differential effects of drugs upon hematopoiesis can be assessed in long-term bone marrow cultures established on nylon screensProceedings of the Society for Experimental Biology and Medicine1992; 199: 481-490.
9.
Noble C., Sina JFUsefulness of the in vitro bone marrow colony-forming assay in cellular toxicologyIn Vitro Toxicology1993 ; 6: 187-195.
10.
Parent-Massin D. et al. Relevance of in vitro studies in drug-induced agranulocytosis. Report of 14 casesDrug Safety1993; 9: 461-469.
11.
Parent-Massin D., Thouvenot D.In vitro study of pesticide hematotoxicity in human and rat progenitorsJournal of Pharmacology and Toxicological Methods1993; 30: 203-207.
12.
Parent-Massin D. et al.Toxicological evaulation of semi-refined carrageenans by two models of cell culture: hepatocytes and hematopoietic progenitors from ratSciences des Aliments1993; 13: 305- 310.
13.
Parent-Massin D., Fuselier R., Thouvenot D.In vitro toxicity of trichothecenes on human haematopoietic progenitorsFood Additives and Contaminants1994; 11: 441-447.
14.
Parent-Massin D., Thouvenot D., Rio B., Riché C.Lindane haematotoxicity confirmed by in vitro tests on human and rat progenitorsHuman and Experimental Toxicology1994; 13 : 103-106.
15.
Parchment RE , Huang M., Erickson-Miller CLRoles for in vitro myelotoxicity tests in preclinical drug development and clinical trial planningToxicologic Pathology1993; 21: 241-250.
16.
Deldar A., House RV, Wierda D.Bone marrow colony-forming assaysMethods in Immunotoxicology1995; 1: 227-250.
17.
Ibrahim NG, Lutton JD, Levere RDThe role of haem biosynthetic and degradative enzymes in erythroid colony development: the effect of haeminBrilish Journal of Haematology1982; 50: 17-28.
18.
Bradford MMA rapid and sensitive method for quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry1976 ; 72: 248-254.
19.
Van Kampen EJ, Ziljstra WGStandardization of hemoglobinometry. II. The hemiglobincyanide methodClinica Chimica Acta1961; 6: 538-544.
20.
Prasad Ark, Dailey HAGeneration of resistance to the diphenyl ether herbicide acifluorfen by MEL cellsBiochemical and Biophysical Research Communications1995; 215: 186-191.
21.
Lambert R., Kroneck Pmh, Böger P.Radical formation and peroxidative activity of diphenyl ethersZeitschift für Naturforschung1984; 39c: 486-491.
22.
Girotti AW, Deziel MRPhotodynamic action of protoporphyrin resealed erythrocyte membranes: mechanism of release of trapped markers In Porphyrin Photosensitization. Kessel D & Dougherty TJ (eds.), Plenum Press , New York, 1983; pp. 213-225.
23.
Schmid R., Schwartz S., Watson CJPorphyrin content of bone marrow and liver in the various formsArchives of Internal Medicine1954; 93: 167-190.
24.
Butler EG et al.Induction of hepatic peroxisome proliferation in mice by lactofen, a diphenyl ether herbicideToxicology and Applied Pharmacology1988; 93: 72-80.
25.
Jacobs JM et al.Effects of diphenyl ether herbicides on porphyrin accumulation by cultured hepatocytesJournal of Biochemical Toxicology1992; 7 : 87-95.
26.
Krijt J. et al.Effect of diphenyl ether herbicides and oxadiazon on porphyrin biosynthesis in mouse liver, rat primary hepatocyte culture and HepG2 cellsArchives of Toxicology1993; 67: 255-261.
27.
Nichol AW, Elsbury S., Angel LA, Elder GHThe site of inhibition of porphyrin biosynthesis by an isomer of diazinon in ratBiochemical Pharmacology1983 ; 32: 2653-2657.
Bleakly P., Nichol AW, Collins AGDiazinon and Porphyria Cutanea TardaMedical Journal of Australia1979; 1 : 314 - 315.
30.
Collins AG, Nichol AW, Elsbury S.Porphyria Cutanea Tarda and argricultural pesticidesAustralian Journal of Dermatology1982; 23: 70-75.
31.
Elder GHPorphyria caused by hexachlorobenzene and other polyhalogenated aromatic hydrocarbonsHandbuch der Experimentallen Pharmakologie1978; 44: 157-200.
