4-Hydroxytamoxifen Gives DNA Adducts by Chemical Activation, but Not in Rat Liver Cells
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- 作者：Martin R. Osborne ; Warren Davis ; Alan J. Hewer ; Ian R. Hardcastle ; and David H. Phillips
- 刊名：Chemical Research in Toxicology
- 出版年：1999
- 出版时间：February 1999
- 年：1999
- 卷：12
- 期：2
- 页码：151 - 158
- 全文大小：184K
- 年卷期：v.12,no.2(February 1999)
- ISSN：1520-5010
文摘
The drug tamoxifen shows evidence of genotoxicity, and induces liver tumors in rats. CovalentDNA adducts have been detected in the liver of rats treated with tamoxifen, and in rathepatocytes in culture. These arise primarily from its metabolite 
-hydroxytamoxifen, andmay also arise, in part, from another metabolite, 4-hydroxytamoxifen. We have prepared twomodel compounds for the potential reactive metabolite formed from 4-hydroxytamoxifen inrat liver. One of these was its -acetoxy ester. This was much more reactive than that fromtamoxifen, and could not be isolated in pure form. It reacted with DNA in the same way that-acetoxytamoxifen did, to give adducts which were isolated by hydrolysis and chromatography,and identified as alkyldeoxyguanosines. The second derivative was ,
-dehydro-4-hydroxytamoxifen. This also reacts with DNA in vitro, to give the same products as those from-acetoxy-4-hydroxytamoxifen. Reaction probably proceeds through the same resonance-stabilized carbocation in either case. However, when primary cultures of rat hepatocytes weretreated with either 4-hydroxytamoxifen, 4,-dihydroxytamoxifen, or ,-dehydro-4-hydroxytamoxifen at a concentration of 10 
M, no adducts could be detected in their DNA by the 32P-postlabeling technique. Similarly, no adducts could be found in the liver DNA of female FischerF344 rats treated orally (at 0.12 mmol kg-1) with the same substances. If 4-hydroxytamoxifenis metabolized to 4,-dihydroxytamoxifen in rat liver, then either this substance is not convertedto reactive esters or they are rapidly detoxified.
-hydroxytamoxifen, andmay also arise, in part, from another metabolite, 4-hydroxytamoxifen. We have prepared twomodel compounds for the potential reactive metabolite formed from 4-hydroxytamoxifen inrat liver. One of these was its -acetoxy ester. This was much more reactive than that fromtamoxifen, and could not be isolated in pure form. It reacted with DNA in the same way that-acetoxytamoxifen did, to give adducts which were isolated by hydrolysis and chromatography,and identified as alkyldeoxyguanosines. The second derivative was ,-dehydro-4-hydroxytamoxifen. This also reacts with DNA in vitro, to give the same products as those from-acetoxy-4-hydroxytamoxifen. Reaction probably proceeds through the same resonance-stabilized carbocation in either case. However, when primary cultures of rat hepatocytes weretreated with either 4-hydroxytamoxifen, 4,-dihydroxytamoxifen, or ,-dehydro-4-hydroxytamoxifen at a concentration of 10 M, no adducts could be detected in their DNA by the 32P-postlabeling technique. Similarly, no adducts could be found in the liver DNA of female FischerF344 rats treated orally (at 0.12 mmol kg-1) with the same substances. If 4-hydroxytamoxifenis metabolized to 4,-dihydroxytamoxifen in rat liver, then either this substance is not convertedto reactive esters or they are rapidly detoxified.