Inhibition of insulin metabolism by hydroxychloroquine and its enantiomers in cytosolic fraction of liver homogenates from healthy and diabetic rats

被引:27
作者
Emami, J [1 ]
Pasutto, FM [1 ]
Mercer, JR [1 ]
Jamali, F [1 ]
机构
[1] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada
关键词
hydroxychloroquine; insulin; metabolism; sugar; enantiomers; stereochemistry; diabetic rats;
D O I
10.1016/S0024-3205(98)00568-2
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
To elucidate the mechanism by which hydroxychloroquine (HCQ) affects glucose metabolism, the effect of this drug and its enantiomers on insulin metabolism was studied using the cytosolic fraction of liver homogenates from healthy and diabetic rats. Eadie-Hofstee plots were monophasic suggesting that only a one-component enzyme system is involved in insulin degradation in the fraction used. Reaction velocity (V) vs substrate concentration plots were consistent with a V-max model. HCQ caused a significant reduction in V-max and V-max/K-m values in both healthy (V-max, 3.63 +/- 0.46 vs 1.97 +/- 0.13, ng/min/mg; protein P < 0.001; and V-max/K-m, 0.265 +/- 0.015 vs 0.112 +/- 0.004, ml/min/g protein) and diabetic rats (V-max, 0.718 +/- 0.06 vs 0.360 +/- 0.024, ng/min/mg protein; and V-max/K-m, 0.05 +/- 0.002 vs 0.023 +/- 0.001, ml/min/g protein). Significant reduction in the V was observed in the presence of racemic (rac)-, R-, or S-HCQ. Ranking of the inhibitory potency was HCQ > S = R except at highest examined concentration (20 mg/mL) which was HCQ > S > R. In conclusion, the effect of HCQ on insulin degradation appears to be, in part, through inhibition of cytosolic insulin metabolizing enzyme. The effect is not stereoselective except at high concentrations. The R- and S-HCQ may have synergistic effects on inhibition of insulin degradation.
引用
收藏
页码:325 / 335
页数:11
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