Sex-Dependent Disposition of Acetaminophen Sulfate and Glucuronide in the in Situ Perfused Mouse Liver
Sex-Dependent Disposition of Acetaminophen Sulfate and Glucuronide in the in Situ Perfused Mouse Liver
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DOI：
10.1124/dmd.109.026815
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发表时间：
2009-09-01
影响因子：
3.9
通讯作者：
Brouwer, Kim L. R.
中科院分区：
文献类型：
--
作者：
Lee, Jin Kyung;Abe, Koji;Brouwer, Kim L. R.
乳腺癌耐药蛋白（BCRP，ABCG 2）在肝小管膜中表达，并介导外源性物质（包括某些化合物的硫酸盐和葡糖苷酸代谢物）的胆汁排泄。肝脏Bcrp表达具有性别依赖性，雄性小鼠表达更高。在本研究中，使用对乙酰氨基酚（APAP）和产生的APAP葡糖苷酸（AG）和硫酸盐（AS）代谢物，在雄性和雌性野生型和Abcg（-/-）（Bcrp缺陷型）小鼠的单次原位灌注肝脏中，对性别依赖性Bcrp表达影响II相代谢物肝胆处置的假设进行了测试。药代动力学模型用于估计控制APAP、AG和AS的肝胆处置的参数。在野生型小鼠中，雄性AS和AG的胆汁排泄速率常数分别是雌性的2.5倍和7倍，反映了雄性主导的Bcrp表达。在Bcrp缺陷小鼠中未观察到AG胆汁排泄的性别依赖性差异，AS胆汁排泄可忽略不计。有趣的是，在野生型小鼠中观察到AG（雄性较高）和AS（雌性较高）的性别依赖性基底外侧排泄，Bcrp缺陷小鼠肝脏中的趋势相似，反映了雄性小鼠肝脏中AG形成和雌性小鼠肝脏中AS形成的速率常数增加。此外，AS基底侧排泄的速率常数在雌性小鼠肝脏中比在雄性小鼠肝脏中显著增加。值得注意的是，多药耐药相关蛋白4在雌性小鼠肝脏中高于雄性小鼠肝脏。总之，性别依赖性差异的共轭和转运蛋白的表达导致了深刻的差异，在肝胆处置的AG和AS在雄性和雌性小鼠肝脏。
Breast cancer resistance protein (BCRP, ABCG2) is expressed in the hepatic canalicular membrane and mediates biliary excretion of xenobiotics including sulfate and glucuronide metabolites of some compounds. Hepatic Bcrp expression is sex-dependent, with higher expression in male mice. The hypothesis that sex-dependent Bcrp expression influences the hepatobiliary disposition of phase II metabolites was tested in the present study using acetaminophen (APAP) and the generated APAP glucuronide (AG) and sulfate (AS) metabolites in single-pass in situ perfused livers from male and female wildtype and Abcg(-/-) (Bcrp-deficient) mice. Pharmacokinetic modeling was used to estimate parameters governing the hepatobiliary disposition of APAP, AG, and AS. In wild-type mice, the biliary excretion rate constant was 2.5- and 7-fold higher in males than in females for AS and AG, respectively, reflecting male-predominant Bcrp expression. Sex-dependent differences in AG biliary excretion were not observed in Bcrp-deficient mice, and AS biliary excretion was negligible. Interestingly, sex-dependent basolateral excretion of AG (higher in males) and AS (higher in females) was noted in wild-type mice with a similar trend in Bcrp-deficient mouse livers, reflecting an increased rate constant for AG formation in male and AS formation in female mouse livers. In addition, the rate constant for AS basolateral excretion was increased significantly in female mouse livers compared with that in male mouse livers. It is interesting to note that multidrug resistance-associated protein 4 was higher in female than in male mouse livers. In conclusion, sex-dependent differences in conjugation and transporter expression result in profound differences in the hepatobiliary disposition of AG and AS in male and female mouse livers.