Saturation toxicokinetics of thioacetamide: Role in initiation of liver injury

被引:106
作者
Chilakapati, J
Shankar, K
Korrapati, MC
Hill, RA
Mehendale, HM
机构
[1] NE Louisiana Univ, Coll Pharm, Dept Toxicol, Monroe, LA 71209 USA
[2] NE Louisiana Univ, Coll Pharm, Div Basic Pharmaceut Sci, Monroe, LA 71209 USA
[3] Arkansas Childrens Nutr Ctr, Little Rock, AR USA
关键词
D O I
10.1124/dmd.105.005520
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Thioacetamide ( TA), a potent centrilobular hepatotoxicant, undergoes a two-step bioactivation mediated by microsomal CYP2E1 to TA sulfoxide (TASO), and further to TA-S, S-dioxide (TASO(2)), a reactive metabolite that initiates cellular necrosis. Our earlier studies showed that bioactivation-mediated liver injury of TA is not dose-proportional. The objective of this study was to examine whether increasing doses of TA lead to enzyme saturation, thereby resulting in lack of dose-response for injury: bioactivation of TA 3 TASO 3 TASO2 may follow zero-order kinetics. A 12-fold dose range of TA (50, 300, and 600 mg/kg i.p.) was injected into male Sprague-Dawley rats. TA and TASO were quantified in plasma, liver, and urine by high-performance liquid chromatography. With increasing doses, the apparent elimination half-lives of TA and TASO increased linearly, indicating that TA bioactivation exhibits saturation kinetics. Increasing TA dose resulted in greater-than-proportional increases in plasma TA and TASO levels. The TASO/TA ratio was inversely proportional to the dose of TA. Covalent binding of C-14-TA-derived radiolabel to liver macromolecules showed a less-than-dose-proportionate increase with a 12-fold higher dose. Less than dose-proportional covalent binding was confirmed in liver microsomal incubations with C-14-TA. Three-fold higher excretion of TASO was seen in urine at the highest dose (600 mg/kg) compared with the lowest dose (50 mg TA/kg). Incubation of TA with rat liver microsomes and purified baculovirus- expressed rat and human CYP2E1 Supersomes, over a concentration range of 0.01 to 10 mM, revealed saturation of TA conversion to TASO at and above 0.05 mM TA concentration, comparable to in vivo plasma and liver levels achieved upon administration of higher doses. Calculated Km values for TA (0.1 mM) and TASO (0.6 mM) suggest that the second step of TA bioactivation is 6-fold less efficient. Collectively, the findings indicate saturation of CYP2E1 at the first (TA to TASO) and second (TASO to TASO(2)) steps of TA bioactivation.
引用
收藏
页码:1877 / 1885
页数:9
相关论文
共 36 条
  • [1] Cholangiocarcinoma and liver cirrhosis in relation to changes due to thioacetamide
    Al-Bader, A
    Mathew, TC
    Abul, H
    Al-Sayer, H
    Singal, PK
    Dashti, HM
    [J]. MOLECULAR AND CELLULAR BIOCHEMISTRY, 2000, 208 (1-2) : 1 - 10
  • [2] BARKER EA, 1974, AM J PATHOL, V74, P575
  • [3] BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
  • [4] NUTRITIONAL IMPACT ON THE FINAL OUTCOME OF LIVER-INJURY INFLICTED BY MODEL HEPATOTOXICANTS - EFFECT OF GLUCOSE LOADING
    CHANDA, S
    MEHENDALE, HM
    [J]. FASEB JOURNAL, 1995, 9 (02) : 240 - 245
  • [5] ROLE OF NUTRITIONAL FATTY-ACID AND L-CARNITINE IN THE FINAL OUTCOME OF THIOACETAMIDE HEPATOTOXICITY
    CHANDA, S
    MEHENDALE, HM
    [J]. FASEB JOURNAL, 1994, 8 (13) : 1061 - 1068
  • [6] Chu C J, 2000, Zhonghua Yi Xue Za Zhi (Taipei), V63, P263
  • [7] The role of cytochrome P450 2E1 in the species-dependent biotransformation of 1,2-dichloro-1,1,2-trifluoroethane in rats and mice
    Dekant, W
    Assmann, M
    Urban, G
    [J]. TOXICOLOGY AND APPLIED PHARMACOLOGY, 1995, 135 (02) : 200 - 207
  • [8] POTENTIATION OF THIOACETAMIDE-INDUCED HEPATOTOXICITY IN ALLOXAN-DIABETIC AND STREPTOZOTOCIN-DIABETIC RATS
    ELHAWARI, AM
    PLAA, GL
    [J]. TOXICOLOGY LETTERS, 1983, 17 (3-4) : 293 - 300
  • [9] GONZALEZ FJ, 1991, ALCOHOL ALCOHOLISM, P97
  • [10] HUNTER AL, 1977, J PHARMACOL EXP THER, V200, P439