(R)-(+)-Menthofuran is a potent, mechanism-based inactivator of human liver cytochrome P450 2A6.
(R)-(+)-Menthofuran is a potent, mechanism-based inactivator of human liver cytochrome P450 2A6.
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发表时间：
1998-07
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通讯作者：
S. Khojasteh-Bakht;L. Koenigs;Raimund M. Peter;William Trager;Sidney D. Nelson
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作者：
S. Khojasteh-Bakht;L. Koenigs;Raimund M. Peter;William Trager;Sidney D. Nelson
(R)-(+）-薄荷呋喃是一种有效的，基于机制的人肝细胞色素P450（CYP 450或P450）2A 6灭活剂。Menthofuran引起CYP 2A 6活性的时间和浓度依赖性损失。CYP 2A 6的失活特征为人肝微粒体的Ki为2.5 microM，kinact为0.22 min-1，纯化表达的CYP 2A 6的Ki为0.84 microM，kinact为0.25 min-1。添加各种亲核试剂、铁螯合剂或活性氧清除剂或广泛透析未能保护CYP 2A 6免于失活。一种抗薄荷呋喃的疑似反应性代谢物的金属硫蛋白缀合物的抗体用于检测与CYP 2A 6的反应性薄荷呋喃代谢物加合物。这些加合物仅在NADPH-P450还原酶和NADPH存在下形成。然而，谷氨酸、甲氧基胺和氨基脲并不能阻止反应性薄荷呋喃代谢物与CYP 2A 6的加合。薄荷呋喃代谢产物形成/CYP 2A 6灭活分配比确定为3.5 +/- 0.6 nmol/nmol P450。薄荷呋喃不能以时间和浓度依赖性方式抑制CYP 1A 2、CYP 2D 6、CYP 2 E1或CYP 3A 4。
(R)-(+)-Menthofuran is a potent, mechanism-based inactivator of human liver cytochrome P450 (CYP or P450) 2A6. Menthofuran caused a time- and concentration-dependent loss of CYP2A6 activity. The inactivation of CYP2A6 was characterized by a Ki of 2.5 microM and a kinact of 0.22 min-1 for human liver microsomes and a Ki of 0.84 microM and a kinact of 0.25 min-1 for purified expressed CYP2A6. Addition of various nucleophiles, a chelator of iron, or scavengers of reactive oxygen species or extensive dialysis failed to protect CYP2A6 from inactivation. An antibody to metallothionein conjugates of a suspected reactive metabolite of menthofuran was used to detect reactive menthofuran metabolite adducts with CYP2A6. These adducts were formed only in the presence of NADPH-P450 reductase and NADPH. Glutathione, methoxylamine, and semicarbazide did not prevent adduction of reactive menthofuran metabolites to CYP2A6, however. The menthofuran metabolite formation/CYP2A6 inactivation partition ratio was determined to be 3.5 +/- 0.6 nmol/nmol of P450. Menthofuran was unable to inactivate CYP1A2, CYP2D6, CYP2E1, or CYP3A4 in a time- and concentration-dependent manner.