Utilization of Human Liver Microsomes to Explain Individual Differences in Paclitaxel Metabolism by CYP2C8 and CYP3A4
Paclitaxel is widely used for treatment of malignant tumors. Paclitaxel is metabolized by CYP2C8 and CYP3A4, and these enzymes are known to differ between individuals, although the details have not been clarified. Recent progress in pharmacogenetics has shown that genetic polymorphisms of metabolic...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2005-01-01
|
Series: | Journal of Pharmacological Sciences |
Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861319322972 |
id |
doaj-a229d88807d34ff09903b1a323916694 |
---|---|
record_format |
Article |
spelling |
doaj-a229d88807d34ff09903b1a3239166942020-11-25T01:52:44ZengElsevierJournal of Pharmacological Sciences1347-86132005-01-019718390Utilization of Human Liver Microsomes to Explain Individual Differences in Paclitaxel Metabolism by CYP2C8 and CYP3A4Ryoko Taniguchi0Toshio Kumai1Naoki Matsumoto2Minoru Watanabe3Koji Kamio4Satoshi Suzuki5Shinichi Kobayashi6Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan; Corresponding author. FAX: +81-44-975-0509 E-mail: yakuri@marianna-u.ac.jpDepartment of Pharmacology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, JapanDepartment of Pharmacology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, JapanDepartment of Pharmacology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, JapanDepartment of Pharmacology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, JapanNon-Profit Organization Human & Animal Bridging Research Organization, 5-11-13, Sugano, Ichikawa, Chiba 272-8513, JapanDepartment of Pharmacology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, JapanPaclitaxel is widely used for treatment of malignant tumors. Paclitaxel is metabolized by CYP2C8 and CYP3A4, and these enzymes are known to differ between individuals, although the details have not been clarified. Recent progress in pharmacogenetics has shown that genetic polymorphisms of metabolic enzymes are related to these individual differences. We investigated the effect of the polymorphisms on paclitaxel metabolism by analyzing metabolic activities of CYP2C8 and CYP3A4 and expressions of mRNA and protein. Production of 6α-hydroxypaclitaxel, a metabolite of CYP2C8, was 2.3-fold larger than 3′-p-hydroxypaclitaxel, a metabolite of CYP3A4. Significant inter-individual differences between these two enzyme activities were shown. The expressions of mRNA and protein levels correlated well with the enzyme activities, especially with CYP3A4. Although it was previously reported that CYP2C8*3 showed lower activity than the wild type, two subjects that had the CYP2C8*3 allele did not show lower activities in our study. Inter-individual differences in paclitaxel metabolism may be related to CYP2C8 and CYP3A4 mRNA expression. CYP2C8 is the primary metabolic pathway of paclitaxel, but there is a “shifting phenomenon” in the metabolic pathway of paclitaxel in the liver of some human subjects. Keywords:: liver, paclitaxel, CYP, polymorphism, individual differencehttp://www.sciencedirect.com/science/article/pii/S1347861319322972 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ryoko Taniguchi Toshio Kumai Naoki Matsumoto Minoru Watanabe Koji Kamio Satoshi Suzuki Shinichi Kobayashi |
spellingShingle |
Ryoko Taniguchi Toshio Kumai Naoki Matsumoto Minoru Watanabe Koji Kamio Satoshi Suzuki Shinichi Kobayashi Utilization of Human Liver Microsomes to Explain Individual Differences in Paclitaxel Metabolism by CYP2C8 and CYP3A4 Journal of Pharmacological Sciences |
author_facet |
Ryoko Taniguchi Toshio Kumai Naoki Matsumoto Minoru Watanabe Koji Kamio Satoshi Suzuki Shinichi Kobayashi |
author_sort |
Ryoko Taniguchi |
title |
Utilization of Human Liver Microsomes to Explain Individual Differences in Paclitaxel Metabolism by CYP2C8 and CYP3A4 |
title_short |
Utilization of Human Liver Microsomes to Explain Individual Differences in Paclitaxel Metabolism by CYP2C8 and CYP3A4 |
title_full |
Utilization of Human Liver Microsomes to Explain Individual Differences in Paclitaxel Metabolism by CYP2C8 and CYP3A4 |
title_fullStr |
Utilization of Human Liver Microsomes to Explain Individual Differences in Paclitaxel Metabolism by CYP2C8 and CYP3A4 |
title_full_unstemmed |
Utilization of Human Liver Microsomes to Explain Individual Differences in Paclitaxel Metabolism by CYP2C8 and CYP3A4 |
title_sort |
utilization of human liver microsomes to explain individual differences in paclitaxel metabolism by cyp2c8 and cyp3a4 |
publisher |
Elsevier |
series |
Journal of Pharmacological Sciences |
issn |
1347-8613 |
publishDate |
2005-01-01 |
description |
Paclitaxel is widely used for treatment of malignant tumors. Paclitaxel is metabolized by CYP2C8 and CYP3A4, and these enzymes are known to differ between individuals, although the details have not been clarified. Recent progress in pharmacogenetics has shown that genetic polymorphisms of metabolic enzymes are related to these individual differences. We investigated the effect of the polymorphisms on paclitaxel metabolism by analyzing metabolic activities of CYP2C8 and CYP3A4 and expressions of mRNA and protein. Production of 6α-hydroxypaclitaxel, a metabolite of CYP2C8, was 2.3-fold larger than 3′-p-hydroxypaclitaxel, a metabolite of CYP3A4. Significant inter-individual differences between these two enzyme activities were shown. The expressions of mRNA and protein levels correlated well with the enzyme activities, especially with CYP3A4. Although it was previously reported that CYP2C8*3 showed lower activity than the wild type, two subjects that had the CYP2C8*3 allele did not show lower activities in our study. Inter-individual differences in paclitaxel metabolism may be related to CYP2C8 and CYP3A4 mRNA expression. CYP2C8 is the primary metabolic pathway of paclitaxel, but there is a “shifting phenomenon” in the metabolic pathway of paclitaxel in the liver of some human subjects. Keywords:: liver, paclitaxel, CYP, polymorphism, individual difference |
url |
http://www.sciencedirect.com/science/article/pii/S1347861319322972 |
work_keys_str_mv |
AT ryokotaniguchi utilizationofhumanlivermicrosomestoexplainindividualdifferencesinpaclitaxelmetabolismbycyp2c8andcyp3a4 AT toshiokumai utilizationofhumanlivermicrosomestoexplainindividualdifferencesinpaclitaxelmetabolismbycyp2c8andcyp3a4 AT naokimatsumoto utilizationofhumanlivermicrosomestoexplainindividualdifferencesinpaclitaxelmetabolismbycyp2c8andcyp3a4 AT minoruwatanabe utilizationofhumanlivermicrosomestoexplainindividualdifferencesinpaclitaxelmetabolismbycyp2c8andcyp3a4 AT kojikamio utilizationofhumanlivermicrosomestoexplainindividualdifferencesinpaclitaxelmetabolismbycyp2c8andcyp3a4 AT satoshisuzuki utilizationofhumanlivermicrosomestoexplainindividualdifferencesinpaclitaxelmetabolismbycyp2c8andcyp3a4 AT shinichikobayashi utilizationofhumanlivermicrosomestoexplainindividualdifferencesinpaclitaxelmetabolismbycyp2c8andcyp3a4 |
_version_ |
1724993369264881664 |