Effects of cytochrome P450 inducers on tamoxifen genotoxicity in female mice in vivo
Effects of cytochrome P450 inducers on tamoxifen genotoxicity in female mice in vivo
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DOI：
10.1016/s0006-2952(96)00875-1
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发表时间：
1997-03-07
影响因子：
5.8
通讯作者：
Randerath, K
中科院分区：
文献类型：
--
作者：
Moorthy, B;Sriram, P;Randerath, K
我们最近报道了抗雌激素他莫昔芬（TAM）在体内雌性小鼠肝脏中产生两组DNA加合物，通过p -32后标记测量，并提供证据表明4-羟他莫昔芬和α -羟他莫昔芬是近似致癌代谢物，分别导致I组和II组加合物（Randerath等）。[j] .中华医学会医学杂志，1994)。由于细胞色素P450 （CYP）酶在TAM代谢中起着重要的作用，因此在本研究中，我们验证了肝脏CYP酶的诱导可能会深刻影响TAM代谢，导致TAM- dna加合物形成的增加或减少。为此，我们用TAM单独或联合几种经典的CYP诱诱剂，即苯巴比妥（PB）、β -萘黄酮（BNF）和孕烯醇酮-16 α -碳腈（PCN）治疗雌性ICR小鼠，并测定了p -32后标记的TAM- dna加合物的水平和几种CYP依赖性酶的活性。每一种诱导剂都大大降低了II组的水平，但对I组加合物没有影响。TAM诱导肝脏苯丙胺n -去甲基化酶活性，其他酶活性不受影响。当TAM与BNF联合使用时，诱导了乙氧基间苯二酚o -去甲基化酶（EROD） （CYP1A1）和甲氧基间苯二酚o -去甲基化酶（MROD） （CYP1A2）活性的协同诱导。同样，PCN与TAM一起给予可协同诱导EROD和乙基吗啡n -去甲基化酶活性。然而，PB和TAM之间没有协同作用。总体而言，研究结果进一步支持TAM代谢为dna反应性亲电试剂的两种途径的存在，并强烈表明所测试的经典CYP诱导剂增强了TAM对非遗传毒性代谢物的解毒作用。(C) 1997爱思唯尔科学有限公司
We recently reported that administration of the antiestrogen tamoxifen (TAM) gives rise to two groups of DNA adducts in female mouse liver in vivo, as measured by P-32-postlabeling, and provided evidence that 4-hydroxytamoxifen and alpha-hydroxytamoxifen are proximate carcinogenic metabolites leading to group I and group II adducts, respectively (Randerath et nl., Carcinogenesis 15: 2087-2094, 1994). Because cytochrome P450 (CYP) enzymes play an important role in TAM metabolism, in this investigation we tested the hypothesis that induction of liver CYP enzymes may affect TAM metabolism profoundly, resulting in increased or decreased TAM-DNA adduct formation in due. To this end, we treated female ICR mice with TAM either alone or in combination with one of several classic CYP inducers, i.e. phenobarbital (PB), beta-naphthoflavone (BNF), and pregnenolone-16 alpha-carbonitrile (PCN), and determined the levels of P-32-postlabeled TAM-DNA adducts and the activities of several CYP-dependent enzymes. Each of the inducers greatly diminished levels of group II, but did not affect group I adducts. TAM elicited induction of benzphetamine N-demethylase activity in liver, while activities of other enzymes were not affected. TAM, when given in combination with BNF, elicited a synergistic induction of ethoxyresorufin O-deethylase (EROD) (CYP1A1) and methoxyresorufin O-demethylase (MROD) (CYP1A2) activities. Likewise, PCN given along with TAM caused synergistic induction of EROD and ethylmorphine N-demethylase activities. There was no synergism between PB and TAM, however. Overall, the results further support the existence of two pathways of TAM metabolism to DNA-reactive electrophiles and strongly suggest that the classic CYP inducers tested enhance detoxication of TAM to non-genotoxic metabolites. (C) 1997 Elsevier Science Inc.