Abstract
We investigated the hepatotoxicity induced by AQ using a glutathione (GSH)-depleted mice model. Although sole administration of either AQ or l-buthionine-S,R-sulfoxinine (BSO), a well-known GSH synthesis inhibitor, produced no significant hepatotoxicity, combined administration of AQ with BSO induced hepatotoxicity characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Pretreatment of aminobenzotriazole, a nonspecific inhibitor for P450s, completely suppressed the above hepatotoxicity caused by AQ co-treatment with BSO. Administration of radiolabeled AQ in combination with BSO exhibited significantly higher covalent binding to mice liver proteins than that observed after sole dosing of radiolabeled AQ. The results obtained in this GSH-depleted animal model suggest that the reactive metabolite of AQ formed by hepatic P450 binds to liver proteins, and then finally leads to hepatotoxicity. These observations may help to understand the risk factors and the mechanism for idiosyncratic hepatotoxicity of AQ in humans.
Similar content being viewed by others
Abbreviations
- AQ:
-
Amodiaquine
- GSH:
-
Glutathione
- BSO:
-
l-Buthionine-S,R-sulfoxinine
- ALT:
-
Alanine aminotransferase
- ABT:
-
Aminobenzotriazole
- LD50:
-
50% Lethal dose
References
Boyne AF, Ellman GL (1972) A methodology for analysis of tissue sulfhydryl components. Anal Biochem 46:639–653. doi:10.1016/0003-2697(72)90335-1
Clarke JB, Maggs JL, Kitteringham NR, Park BK (1990) Immunogenicity of amodiaquine in the rat. Int Arch Allergy Appl Immunol 91:335–342
Clarke JB, Neftel K, Kitteringham NR, Park BK (1991) Detection of antidrug IgG antibodies in patients with adverse drug reactions to amodiaquine. Int Arch Allergy Appl Immunol 95(4):369–375
Davis SR, Quinlivan EP, Stacpoole PW, Gregory JF 3rd (2006) Plasma glutathione and cystathionine concentrations are elevated but cysteine flux is unchanged by dietary vitamin B-6 restriction in young men and women. J Nutr 136:373–378
Drew R, Miners JO (1984) The effects of buthionine sulfoximine (BSO) on glutathione depletion and xenobiotic biotransformation. Biochem Pharmacol 33:2989–2994. doi:10.1016/0006-2952(84)90598-7
Griffith OW, Meister A (1979) Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J Biol Chem 254:7558–7560
Harrison AC, Kitteringham NR, Clarke JB, Park BK (1992) The mechanism of bioactivation and antigen formation of amodiaquine in the rat. Biochem Pharmacol 43:1421–1430. doi:10.1016/0006-2952(92)90198-R
Hernanz A, Fernández-Vivancos E, Montiel C, Vazquez JJ, Arnalich F (2000) Changes in the intracellular homocysteine and glutathione content associated with aging. Life Sci 67:1317–1324. doi:10.1016/S0024-3205(00)00722-0
Ip C (1984) Comparative effects of antioxidants on enzymes involved in glutathione metabolism. Life Sci 34:2501–2506. doi:10.1016/0024-3205(84)90287-X
Jewell H, Maggs JL, Harrison AC, O’Neill PM, Ruscoe JE, Park B (1995) Role of hepatic metabolism in the bioactivation and detoxication of amodiaquine. Xenobiotica 25:199–217
Lauterburg BH, Velez ME (1988) Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut 2:1153–1157. doi:10.1136/gut.29.9.1153
Masubuchi N, Makino C, Murayama N (2007) Prediction of in vivo potential for metabolic activation of drugs into chemically reactive intermediate: correlation of in vitro and in vivo generation of reactive intermediates and in vitro glutathione conjugate formation in rats and humans. Chem Res Toxicol 20:455–464. doi:10.1021/tx060234h
Matzinger P (2002) The danger model: a renewed sense of self. Science 296:301–305. doi:10.1126/science.1071059
Mizutani T, Satoh K, Nomura H, Nakanishi K (1991) Hepatotoxicity of eugenol in mice depleted of glutathione by treatment with DL-buthionine sulfoximine. Res Commun Chem Pathol Pharmacol 71:219–230
Mizutani T, Irie Y, Nakanishi K (1994a) Styrene-induced hepatotoxicity in mice depleted of glutahione. Res Commun Mol Pathol Pharmacol 86:361–374
Mizutani T, Nakahori Y, Yamamoto K (1994b) p-Dichlorobenzene-induced hepatotoxicity in mice depleted of glutathione treated with buthionine sulfoximine. Toxicology 94:57–67. doi:10.1016/0300-483X(94)90028-0
Mizutani T, Murakami M, Shirai M, Tanaka M, Nakanishi K (1999) Metabolism-dependent hepatotoxicity of Methimazole in mice depleted of glutathione. J Appl Toxicol 19:193–198
Mugford CA, Mortillo M, Mico BA, Tarloff JB (1992) 1-Aminobenzotriazole-induced destruction of hepatic and renal cytochromes P450 in male Sprague-Dawley rats. Fundam Appl Toxicol 19:43–49. doi:10.1016/0272-0590(92)90026-E
Nakamura S, Kugiyama K, Sugiyama S, Miyamoto S, Koide S, Fukushima H, Honda O, Yoshimura M, Ogawa H (2002) Polymorphism in the 5′-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction. Circulation 105:2968–2973. doi:10.1161/01.CIR.0000019739.66514.1E
Phillips-Howard PA, West LJ (1990) Serious adverse drug reactions to pyrimethamine-sulphadoxine, pyrimethamine-dapsone and to amodiaquine in Britain. J R Soc Med 83:82–85
Raymond JM, Dumas F, Baldit C, Couzigou P, Beraud C, Amouretti M (1989) Fatal acute hepatitis due to amodiaquine. J Clin Gastroenterol 11:602–603. doi:10.1097/00004836-198910000-00034
RTECS (1985–1986) Registry of toxic effects of chemical substances. RTECS database (available at http://csi.micromedex.com/)
Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205. doi:10.1016/0003-2697(68)90092-4
Tafazoli S, O’Brien PJ (2009) Amodiaquine-induced oxidative stress in a hepatocyte inflammation model. Toxicology 256:101–109. doi:10.1016/j.tox.2008.11.006
Uetrecht J (1999) New concepts in immunology relevant to idiosyncratic drug reactions: the “danger hypothesis” and innate immune system. Chem Res Toxicol 12:387–395. doi:10.1021/tx980249i
Watanabe T, Sagisaka H, Arakawa S, Shibaya Y, Watanabe M, Igarashi I, Tanaka K, Totsuka S, Takasaki W, Manabe S (2003) A novel model of continuous depletion of glutathione in mice treated with L-buthionine (S, R)-sulfoximine. J Toxicol Sci 28:455–463. doi:10.2131/jts.28.455
Watkins WM, Sixsmith DG, Spencer HC, Boriga DA, Kariuki DM, Kipingor T, Koech DK (1984) Effectiveness of amodiaquine as treatment for chloroquine-resistant Plasmodium falciparum infections in Kenya. Lancet 8373:357–359. doi:10.1016/S0140-6736(84)90410-0
Winstanley PA, Breckenridge AM (1987) Currently important antimalarial drugs. Ann Trop Med Parasitol 81(5):619–627
Acknowledgments
We would like to thank Minoru Inoue and Keiko Okato for preparing the samples for the liver histopathological evaluation. We are also very grateful to Hiroshi Sato for his assistance with the histology.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shimizu, S., Atsumi, R., Itokawa, K. et al. Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice. Arch Toxicol 83, 701–707 (2009). https://doi.org/10.1007/s00204-009-0436-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-009-0436-9