Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Synthesis of Allylthiopyridazine Derivatives and Inhibition of Aflatoxin ${B_1}-Induced$ Hepatotoxicity in Rats

  • Published : 2003.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

Five kinds of allylthiopyridazine derivatives were synthesized and their chemoprotective activities examined in rats exposed to aflatoxin $B_1$-toxicant. Rats were pretreated with five allylthiopyridazine derivatives at daily oral doses of 50 mg/kg for 10 consecutive days, and during this period with one or three repeated doses of the potent hepatotoxin, aflatoxin $B_1$. The hepatoprotective effects of the allylthiopyridazine derivatives against aflatoxin $B_1$ (1 mg/kg, three times at intervals of 3 days, i.p., or at 3 mg/kg, once at final days, i.p.) administration were showed the significantly normal as compared with control in body and liver weights. Aspartate aminotransferase and alanine aminotransferase levels were markedly elevated after aflatoxin $B_1$ administration, and pretreatment with allylthiopyridazine derivatives, before aflatoxin $B_1$ administration, resulted in decreased levels of these enzymes. In addition, the allylthiopyridazine derivatives, K6 (3-methoxy-), K8 (3-chloro-), K16 (3-ethoxy-) and K17 (3-n-propoxy), induced elevated hepatic GSH levels. Four kinds of allylthiopyridazine derivatives investigated were effective against aflatoxin $B_1$ -induced hepatotoxicity.

Keywords

References

  1. Blanchette-Mackie, E. J., Dwyer, N, K., and Amende, L. A., Cytochemical studies of lipid metabolism: immunologold probes for lipidprotein lipase and cholesterol. Am. J. Amat., 185, 255-263 (1989)
  2. Bradford, M. M., A Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 72, 248-254 (1976) https://doi.org/10.1016/0003-2697(76)90527-3
  3. Gallagher, E. P., Wienkers, L. C., Stapleton, P. L., Kunze, K. L., and Eaton, D. L., Role of Human microsomal and human complementary DNA-expressed cytochromes P450 3A4 in the bioactivation of aflatoxin $B_1$. Cancer Res., 54, 101-108 (1994)
  4. Gopalan, P., Tsuji, T., Lehmann, K., Kimura, M., Shinozuka, H., Sato, K., and Lotlikar, P. D., Modulation of aflatoxin $B_1$-induced glutathione S-transferase placental from positive hepatic foci by pretreatment of rats with phenobarbital and buthionine sulfoximine. Carcinogenesis., 14, 1469-1470 (1993) https://doi.org/10.1093/carcin/14.7.1469
  5. Gorelick, N. J., Risk assessment for aflatoxin: I. Metabolism of aflatoxin $B_1$ by different species. Risk. Anal., 10, 539-559 (1990) https://doi.org/10.1111/j.1539-6924.1990.tb00538.x
  6. Gyamfi, M. A. and Anja, Y., Medicinal herb, Thonningia sanguinea protects against aflatoxin $B_1$ acute hepatotoxicity in Fischer rats. Hum. Exp. Toxicol., 17, 418-423 (1996) https://doi.org/10.1191/096032798678909007
  7. Ha, T. G., Jang, J. J., Kim, S. G., and Kim, N. D., 2-(Allylthio) pyrazine inhibition of aflatoxin $B_1$-induced hepatocarcinogenesis in rat. Chem. Biol. Interact., 121, 209-222 (1999) https://doi.org/10.1016/S0009-2797(99)00094-0
  8. Habig, W. H., Pabst, M. J., and Jakoby, W. B., Glutathione Stransferase: the first enzymatic step in mercaturic acid formation, J.Biol. Chem., 249, 7130-7139 (1974)
  9. Ishii, K., Maeda, K., Kamatake, T. and Kato, R., Mutagenic activation of aflatoxin $B_1$ by several forms of purified cytochrom P450. Mutat. Res., 174, 85-88 (1986) https://doi.org/10.1016/0165-7992(86)90095-3
  10. Johnson, W. W. and Guengerich, F. P., Reaction of aflatoxin $B_1$, exo-8.9-epxide with DNA: kinetic analysis of 60 ralent binding and DNA induced hydrolysis. Proc. Natl. Acad. Sci. U.S.A., 94, 6121-6125 (1997) https://doi.org/10.1073/pnas.94.12.6121
  11. Johnson, W. W., Harris, T. M., and Guengerich, F. P., Kinetics and mechanism of hydrolysis of aflatoxin $B_1$ exo-8,9-oxide and rearrangement of the dihydrodiol. J. Am. Chem. Soc., 118, 8213-8220 (1996)
  12. Judah, D. J., Hayes, J. D., Yang, T. C., Lian, L. Y., Roberts, G. K., Famer, P. P., Lamb, T. H., and Neal, G. E., Anorel aldehydereductase with activity towards a metabolite of aflatoxin $B_1$ is expressed in rat liver during carcinogenesis and following the administration of an antioxidant. Biochem. J., 292, 13-18 (1993) https://doi.org/10.1042/bj2920013
  13. Jung, M. Y., Kwon, S. K., and Moon, A., Chemopreventive allylthiopyridazine derivatives induce apoptosis in SK-Hep-1 hepatocarcinoma cells through a caspase-3-dependent mechanism. Eur. J. Cancer, 37, 2104-2110 (2001) https://doi.org/10.1016/S0959-8049(01)00242-8
  14. Knight, L. P., Primiano, T., Groopman, J. D., Kensler, T. W., and Sutter, T. R., cDNA cloning, expression and activity of a second human aflatoxin $B_1$-metabolizing member of the aldoketo reductase superfamily, AKR7A3. Carcinogenesis, 20, 1215-23 (1999) https://doi.org/10.1093/carcin/20.7.1215
  15. Kwon, S. K., Synthesis of 4,5-substituted 3-alkoxy-6-allylthiopyridazine derivatives. Yakhak Hoeji, 46, 155-160 (2002)
  16. Lee, J. I., Park, H., Yun, Y., S. and Kwon, S. K., An efficient synthesis of 3-alkoxy-6-allylthiopyridazines. J. Kor. Chem. Soc., 45, 386-390 (2001)
  17. Lowery, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. T., Protein measurement with the folin phenol reagent. J. Biol. Chem., 193, 295-275 (1951)
  18. Manson, M. M., Bell, H. W. L., Barrett, M. C., Clark, H. L., Judah, J. J., Williamson, G., and Neal, G. E., Mechanism of action of dietary chemoprotective agents in rat liver: induction of phase I and phase II drug metabolizing enzymes and aflatoxin $B_1$ metabolism. Carcinogenesis, 18, 1729-1738 (1997) https://doi.org/10.1093/carcin/18.9.1729
  19. Manson, M. M., Hudson, E. A., Ball, H. W., Burrett, M. C., Clack, H. L., Judah, D. J., Verschoyle, R. D., and Neal, G. E., Chemoprevention of aflatoxin $B_1$-induced carcinogenesis by indole-s-carbinol in rat liver-predicting the outcome using early biomarkers. Carcinogenesis, 1829-1836 (1998)
  20. Metcalfe, S. A., Colley, P. J., and Neul, G. E., A comparison of the effects of pretreatment with phenobarbitone and 3-methyl cholanthrene an the metabolism of AF$B_1$ by rat liver microsme and isolated hepatocytes in vitro. Chem. Biol. Interact., 35, 145-157 (1981) https://doi.org/10.1016/0009-2797(81)90139-3
  21. Primiano, P. E., Egner, Sutter, T. R., Kelloff, G. J., Roebuck, B. D., and Kensler, Y. W., Intermittent dosing with oltipraz : relationship between chemprevention of aflatoxin-induced tumorigenesis and induction of glutathione S-transferases. Cancer Res., 44, 4319-4324 (1995)
  22. Reitman, S. and Frankel, S., A colorimetric method for the determination of serum glutamic oxaloacetic and glutamic pyruvic transaminase. Am. J. Clin. Pathol., 28, 56-60 (1957) https://doi.org/10.1093/ajcp/28.1.56
  23. Sheweita, S. A., Abd El-Gagar, M., and Bastawy, M., Carbon tetrachloride-induced changes in the activity of phase II drugmetabolizing enzyme in the liver of male rat role of oxidants. Toxicology, 165, 217-224 (2001) https://doi.org/10.1016/S0300-483X(01)00429-2
  24. Toskulkao, C., Yoshida, T., Glinsulkon, T., and Kuroiwa, Y., Potentiation of aflatoxin $B_1$ induced hepatotoxicity in male Wistar rats with ethanol pretreatment. J. Toxicol. Sci., 141, 141-151 (1996)
  25. Towner, R. A., Hashimoto, H., and Summers, P. H., Non-invasive in vivo magnetic resonance imaging assessment of acute aflatoxin $B_1$ hepatotoxicity in rats. Biochim. Biophys. Acta, 1475, 314-320 (2000) https://doi.org/10.1016/S0304-4165(00)00084-2
  26. Ueng, Y. F., Shinada, T., Yamazaki, H., and Guengrich, F. P., Oxidation of aflatoxin $B_1$ by bacterial recombinant Human cytochrome P450 enzymes. Chem. Res. Toxicol., 8, 218-225 (1995) https://doi.org/10.1021/tx00044a006
  27. Wang, J. C., Shen, X., He, X., Zhu, Y. S., Zhang, B. C., Wnag, J. B., Qian, G. S., Kuang, S. Y., Zarba, A., Egaer, D. A., Jacobson, L. P., Munoz, A., Helzlsourer, K. J., Groopman, J. D., and Kensler, T. W., Protective alterations in phase 1 and 2 metabolism of aflatoxin $B_1$ by oltipraz residents of Q1 dong, Peoples Republic of China. J. Natl. Cancer. Inst., 117, 2347-2354 (1999)