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Effects of the oxazolidinedione anticonvulsants trimethadione and dimethadione and the barbiturate homolog 5,5-dimethylbarbituric acid onN-nitrosodiethylamine-initiated renal and hepatic carcinogenesis in the F344/NCr rat

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Abstract

The oxazolidinedione anticonvulsant trimethadione (3,5,5-trimethyl-2,4-oxazolidinedione, TMO) as well as its major metabolite, dimethadione (5,5-dimethyl-2,4-oxazolidinedione, DMO), and a structural analog from the barbiturate series, 5,5-dimethylbarbituric acid (DMB), were fed to F344/NCr male rats previously given a single initiating injection of N-nitrosodiethylamine (NDEA). The known promoter, phenobarbital (5-ethyl-5-phenylbarbituric acid, PB), was employed in this study as a positive control. At dosage levels equimolar to 500 ppm PB, none of the three compounds promoted development of hepatocellular adenomas or carcinomas, in contrast to PB. The two oxazolidinedione analogs and DMB caused minimal or no induction of cytochrome P450 isozyme 2B1 (CYP2B1)-mediated alkoxyresorufin O-dealkylase activities following short-term (2 weeks) feeding to separate groups of 6-week-old male F344/NCr rats, in contrast to the dramatic induction caused by PB. Promotion of neither thyroid nor renal neoplasia was observed following prolonged feeding of any of the tested compounds, although a significantly higher frequency of premalignant renal cortical tubular lesions (dysplasias) was seen in rats exposed to TMO following NDEA initiation than in those treated with NDEA alone. These studies provide important additional data on structure/liver tumor promoting activity relationships, and yield further evidence that within this group of structurally related anticonvulsants, it is possible to separate anticonvulsant activity from tumor promoting activity in the rat liver.

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Abbreviations

CYP1A:

cytochrome P450 isozyme subfamily 1A

CYP2B1:

cytochrome P450 isozyme 2B1

DMB:

5,5-dimethylbarbituric acid

DMO:

dimethadione

LGL:

large granular lymphocytic

NDEA:

N-nitrosodiethylamine

PB:

phenobarbital

TMO:

trimethadione

References

  • Bar-Khayim Y, Teplitz C, Garella S, Chazan JA (1973) Trimethadione (Tridione®)-induced nephrotic syndrome. A report of a case with unique ultrastructural renal pathology. Am J Med 54: 272–280

    Article  PubMed  Google Scholar 

  • Böhlen P, Stein S, Dairman W, Udenfriend S (1973) Fluorometric assay of proteins in the nanogram range. Arch Biochem Biophys 155: 213–220

    PubMed  Google Scholar 

  • Brouillette WJ, Brown GB, DeLorey TM, Shirali SS, Grunewald GL (1988) Anticonvulsant activities of phenyl-substituted bicyclic 2,4-oxazolidinediones and monocyclic models. Comparison with binding to the neuronal voltage-dependent sodium channel. J Med Chem 31: 2218–2221

    Article  PubMed  Google Scholar 

  • Butler TC, Waddell WJ, Poole DT (1965) Demethylation of trimethadione and metharbital by rat liver microsomal enzymes: substrate concentration-yield relationships and competition between substrates. Biochem Pharmacol 14: 937–942

    PubMed  Google Scholar 

  • Campbell HA, Xu Y-D, Hanigan MH, Pitot HC (1986) Application of quantitative stereology to the evaluation of phenotypically heterogenous enzyme-altered foci in the rat liver. J Natl Cancer Inst 76: 751–767

    PubMed  Google Scholar 

  • Chen G, Ensor CR, Clarke IG (1951) Central nervous action of hydantoins, oxazolidinediones and thiazolidones. AMA Arch Neurol Psychiatr 66: 329–337

    Google Scholar 

  • Close WJ, Spielman MA (1961) Anticonvulsant drugs. In: Hartung WH (ed) Medicinal chemistry, Vol. V. John Wiley & Sons, New York, New York, pp 1–349

    Google Scholar 

  • Diwan BA, Palmer AE, Ohshima M, Rice JM (1985a)N-Nitroso-N-methylurea initiation in multiple tissues for organ-specific tumor promotion in rats by phenobarbital. J Natl Cancer Inst 75: 1099–1105

    PubMed  Google Scholar 

  • Diwan BA, Rice JM, Ohshima M, Ward JM, Dove LF (1985b) Comparative tumor-promoting activities of phenobarbital, amobarbital, barbital sodium and barbituric acid on livers and other organs of male F344/NCr rats following initiation withN-nitrosodiethylamine. J Natl Cancer Inst 74: 509–516

    PubMed  Google Scholar 

  • Diwan BA, Rice JM, Hu H, Ward JM (1986) Barbiturate structure/tumor promotion relationships: tumor promoting effects of two long-acting hypnotic barbiturates, 5,5-diallylbarbituric acid and 5-allyl-5-isopropylbarbituric acid, and two monosubstituted analogs of phenobarbital, 5-ethyl- and 5-phenylbarbituric acid in rat liver. Proc Am Assoc Cancer Res 27: 141

    Google Scholar 

  • Diwan BA, Nims RW, Lubet RA, Rice JM (1987) Liver tumor promoting activity of phenobarbital is associated with its ability to induce phenobarbital-inducible cytochrome(s) P-450 (P-450PB-B), aminopyrineN-demethylase activity and liver hypertrophy. Toxicologist 7: 106

    Google Scholar 

  • Diwan BA, Rice JM, Nims RW, Lubet RA, Hu H, Ward JM (1988) P-450 enzyme induction by 5-ethyl-5-phenylhydantoin and 5,5-diethylhydantoin, analogues of barbiturate tumor promoters phenobarbital and barbital, and promotion of liver and thyroid carcinogenesis initiated byN-nitrosodiethylamine in rats. Cancer Res 48: 2492–2497

    PubMed  Google Scholar 

  • Diwan BA, Nims RW, Ward JM, Hu H, Lubet RA, Rice JM (1989) Tumor promoting activities of ethylphenylacetylurea and diethylacetylurea, the ring hydrolysis products of barbiturate tumor promoters phenobarbital and barbital, in rat liver and kidney initiated byN-nitrosodiethylamine. Carcinogenesis 10: 189–194

    PubMed  Google Scholar 

  • Dunnett CW (1955) A multiple comparison procedure for comparing several treatments with a control. J Am Statist Assoc 50: 1096–1121

    Google Scholar 

  • Everett GM, Richards RK (1944) Comparative anticonvulsive action of 3,5,5-trimethyloxazolidine-2,4-dione (Tridione), dilantin and phenobarbital. J Pharmacol Exp Ther 81: 402–407

    Google Scholar 

  • Everett GM, Richards RK (1945) Comparative anticonvulsant and hypnotic action of some barbituric acid derivatives. Fed Proc 4: 20

    Google Scholar 

  • Hagiwara A, Diwan BA, Ward JM (1989) Barbital sodium, a tumor promoter for kidney tubules, urinary bladder, and liver of the F344 rat, induces persistent increases in levels of DNA synthesis in renal tubules but not in urinary bladder epithelium or hepatocytes. Fundam Appl Toxicol 13: 332–340

    Article  PubMed  Google Scholar 

  • Heymann W, Hackel DB, Hunter JLP (1960) Trimethadione (Tridione®) nephrosis in rats. Pediatrics 25: 112–118

    PubMed  Google Scholar 

  • Hiasa Y, Ohshima M, Iwata C, Tanikake T (1979) Histopathological studies on renal tubular cell tumors in rats treated with N-ethyl-N-hydroxyethylnitrosamine. Gann 70: 817–820

    PubMed  Google Scholar 

  • Institute of Laboratory Animal Resources, National Research Council, National Academy of Sciences (1980) Histologic typing of liver tumors of the rat. J Natl Cancer Inst 64: 177–206

    Google Scholar 

  • Konishi N, Ward JM (1989) Increased levels of DNA synthesis in hyperplastic renal tubules of aging nephropathy in female F344/NCr rats. Vet Pathol 26: 6–10

    PubMed  Google Scholar 

  • Leonard TB, Dent JG, Graichen ME, Lyght O, Popp JA (1982) Comparison of hepatic carcinogen initiation-promotion systems. Carcinogenesis 8: 851–856

    Google Scholar 

  • Lubet RA, Nims RW, Mayer RT, Cameron JW, Schechtman LM (1985) Measurement of cytochrome P-450 dependent dealkylation of alkoxyphenoxazones in hepatic S9s and hepatocyte homogenates: effects of dicumarol. Mutat Res 142: 127–131

    Article  PubMed  Google Scholar 

  • Lubet RA, Nims RW, Rice JM, Ward JM, Diwan BA (1988) Induction of epoxide hydrolase and specific forms of cytochrome P-450 and its association with liver tumor promotion: species comparison employing phenobarbital (rat, mouse, hamster, patas monkey) and effects of diverse compounds in the rat. Proc Am Assoc Cancer Res 29: 160

    Google Scholar 

  • Lubet RA, Nims RW, Ward JM, Rice JM, Diwan BA (1989) Induction of cytochrome P450b and its relationship to liver tumor promotion. J Am Coll Toxicol 8: 259–268

    Google Scholar 

  • Nims RW, Devor DE, Henneman JR, Lubet RA (1987) Induction of alkoxyresorufin O-dealkylases, epoxide hydrolase, and liver weight gain: correlation with liver tumor-promoting potential in a series of barbiturates. Carcinogenesis 8: 67–71

    PubMed  Google Scholar 

  • Northway JD, West CD (1967) Successful therapy of trimethadione nephrosis with prednisone and cyclophosphamide. Report of a case. J Pediat 71: 259–261

    PubMed  Google Scholar 

  • Olhagen B, Svanborg A (1953) Attempts to produce experimental lipid nephrosis with Tridione. Scand J Clin Lab Invest 5: 1126–1129

    Google Scholar 

  • Peraino C, Fry RJM, Staffeldt E (1971) Reduction and enhancement of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res 31: 1506–1512

    PubMed  Google Scholar 

  • Peraino C, Fry RJM, Staffeldt E, Christopher JP (1975) Comparative enhancing effects of phenobarbital, amobarbital, diphenylhydantoin, and dichlorodiphenyltrichloroethane on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat. Cancer Res 35: 2884–2890

    PubMed  Google Scholar 

  • Peraino C, Staffeldt EF, Carnes BA, Ludeman VA, Blomquist JA, Vesselinovitch SD (1984) Characterization of histochemically detectable altered hepatocyte foci and their relationship to hepatic tumorigenesis in rats treated once with diethylnitrosamine or benzo(a)pyrene within one day after birth. Cancer Res 44: 3340–3347

    PubMed  Google Scholar 

  • Pereira MA, Savage RE Jr, Herren SL, Guion CW (1982) Comparison of enhancement of GGTase-positive foci and induction of ornithine decarboxylase in rat liver by barbiturates. Carcinogenesis 3: 147–150

    PubMed  Google Scholar 

  • Pereira MA, Herren-Freund SL, Britt AL, Khoury MM (1984) Effect of coadministration of phenobarbital sodium onN-nitrosodiethylamineinduced γ-glutamyltranspeptidase-positive foci and hepatocellular carcinoma in rats. J Natl Cancer Inst 72: 741–744

    PubMed  Google Scholar 

  • Pitot HC (1979) Drugs as promoters of Carcinogenesis. In: Estabrook RW, Lindbaub E (eds) The induction of drug metabolism. Schattaner-Verlag, New York, New York, pp 471–485

    Google Scholar 

  • Rice JM, Diwan BA, Hu H, Ward JM, Nims RW, Lubet RA (1992) Enhancement of hepatocarcinogenesis and induction of specific cytochrome P450-dependent monooxygenase activities by the barbiturates allobarbital, aprobarbital, pentobarbital, secobarbital, and 5-phenyl- and 5-ethylbarbituric acids. Carcinogenesis (in press)

  • Rumler W, Gründig CA, Maaz H-J (1972) über die Korrelation zwischen Proteinurie und Enzymurie bei experimenteller Nierenschädigung der Ratte mit Oxazolidindion. Acta Biol Med Germ 29: 259–262

    PubMed  Google Scholar 

  • Schulte-Hermann R (1985) Tumor promotion in the liver. Arch Toxicol 57: 147–158

    Article  PubMed  Google Scholar 

  • Sinks LF, Parker EC, Boulware JR (1963) Trimethadione nephrosis. Am J Dis Child 105: 198–201

    Google Scholar 

  • Shinozuka H, Lombardi B, Abanobi SE (1982) A comparative study of the efficacy of four barbiturates as promoters of the development of γ-glutamyltranspeptidase-positive foci in the liver of carcinogen treated rats. Carcinogenesis 3: 1017–1020

    PubMed  Google Scholar 

  • Short BG, Burnett VL, Cox MG, Bus JS, Swenberg JA (1987) Site-specific renal cytotoxicity and cell proliferation in male rats exposed to petroleum hydrocarbons. Lab Invest 57: 564–577

    PubMed  Google Scholar 

  • Tanaka E, Yoshida T, Kuroiwa Y (1985) Dose-independent pharmacokinetics of trimethadione and its metabolite in rats. J Pharm Sci 74: 340–341

    PubMed  Google Scholar 

  • Tatematsu M, Nakanishi K, Murasaki G, Miyata Y, Hirose M, Ito N (1979) Enhancing effect of inducers of liver microsomal enzymes on induction of hyperplastic liver nodules byN-2-fluorenylacetamide in rats. J Natl Cancer Inst 63: 1411–1416

    PubMed  Google Scholar 

  • Vida JA (1981) Anticonvulsants. In: Foye WA (ed) Principles of medicinal chemistry. Lea & Febiger, Philadelphia, PA, pp 183–197

    Google Scholar 

  • Waddell WJ, Butler TC (1957) Renal excretion of 5,5-dimethyl-2,4-oxazolidinedione (product of demethylation of trimethadione). Proc Soc Exp Biol Med 96: 563–565

    PubMed  Google Scholar 

  • Withrow CD, Stout RJ, Barton LJ, Beacham WS, Woodbury DM (1968) Anticonvulsant effects of 5,5-dimethyl-2,4-oxazolidinedione (DMO). J Pharmacol Exp Ther 161: 335–341

    Google Scholar 

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Authors and Affiliations

  1. Biological Carcinogenesis and Development Program, PRI/DynCorp, 21702, Frederick, MD, USA

    Bhalchandra A. Diwan & John R. Henneman

  2. Laboratory of Comparative Carcinogenesis, NCI-Frederick Cancer Research and Development Center, 21702, Frederick, MD, USA

    Raymond W. Nims, Jerrold M. Ward, Ronald A. Lubet & Jerry M. Rice

Authors
  1. Bhalchandra A. Diwan
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  2. Raymond W. Nims
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  3. John R. Henneman
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  4. Jerrold M. Ward
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  5. Ronald A. Lubet
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  6. Jerry M. Rice
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Diwan, B.A., Nims, R.W., Henneman, J.R. et al. Effects of the oxazolidinedione anticonvulsants trimethadione and dimethadione and the barbiturate homolog 5,5-dimethylbarbituric acid onN-nitrosodiethylamine-initiated renal and hepatic carcinogenesis in the F344/NCr rat. Arch Toxicol 66, 413–422 (1992). https://doi.org/10.1007/BF02035132

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  • DOI: https://doi.org/10.1007/BF02035132

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