Analysis of two matrix metalloproteinase inhibitors and their metabolites for induction of phospholipidosis in rat and human hepatocytes
ABT-770 [( S)- N-[1-[[4′-trifluoromethoxy-[1,1′-biphenyl]-4-yl]oxy]methyl-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]- N-hydroxyformamide], a matrix metalloproteinase inhibitor (MMPI), produced generalized phospholipidosis in rats. Phospholipid accumulation was accompanied by retention of drug...
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| Veröffentlicht in: | Biochemical pharmacology 2001-12, Vol.62 (12), p.1661-1673 |
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| creator | Gum, Rebecca J. Hickman, Dean Fagerland, Jane A. Heindel, Matthew A. Gagne, Gerard D. Schmidt, James M. Michaelides, Michael R. Davidsen, Steven K. Ulrich, Roger G. |
| description | ABT-770 [(
S)-
N-[1-[[4′-trifluoromethoxy-[1,1′-biphenyl]-4-yl]oxy]methyl-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-
N-hydroxyformamide], a matrix metalloproteinase inhibitor (MMPI), produced generalized phospholipidosis in rats. Phospholipid accumulation was accompanied by retention of drug-related material and was associated with increased mortality. Generation of a successful drug candidate depended upon understanding the cause of the phospholipidosis and redesigning the chemical structure accordingly. ABT-770 and other MMPIs, plus several metabolites of each, were assayed for their ability to induce phospholipidosis in primary cultured rat and human hepatocytes. Phospholipid accumulation was detected by following the incorporation of a fluorescent phospholipid analogue into intracytoplasmic inclusion bodies characteristic of phospholipid storage disorders. At 24 and 48 hr, none of the parent compounds induced phospholipidosis
in vitro in rat or human hepatocytes. Phospholipidosis was associated primarily with an amine metabolite of ABT-770. The amine metabolite of another MMPI, ABT-518 ([
S-(
R∗,
R∗)]-
N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]ethyl]-
N-hydroxyformamide), produced little phospholipidosis in rat and human hepatocytes even at concentrations up to 100 μM. The presence or absence of phospholipidosis in the
in vitro assay correlated well with ultrastructural findings and drug accumulation in rat tissues. ABT-770, which produced phospholipidosis associated with its amine metabolite
in vitro and
in vivo, also generated a higher tissue to plasma distribution of metabolites particularly in tissues where phospholipidosis was observed. ABT-518 and its amine metabolite, however, produced low tissue to plasma ratios and induced little to no phospholipidosis
in vitro or
in vivo. These results demonstrate that the phospholipidosis observed for ABT-770 could be attributed to a cationic metabolite, and that altering the properties of such a metabolite, by modification of the parent compound, alleviated the disorder. |
| doi_str_mv | 10.1016/S0006-2952(01)00823-1 |
| format | Article |
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S)-
N-[1-[[4′-trifluoromethoxy-[1,1′-biphenyl]-4-yl]oxy]methyl-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-
N-hydroxyformamide], a matrix metalloproteinase inhibitor (MMPI), produced generalized phospholipidosis in rats. Phospholipid accumulation was accompanied by retention of drug-related material and was associated with increased mortality. Generation of a successful drug candidate depended upon understanding the cause of the phospholipidosis and redesigning the chemical structure accordingly. ABT-770 and other MMPIs, plus several metabolites of each, were assayed for their ability to induce phospholipidosis in primary cultured rat and human hepatocytes. Phospholipid accumulation was detected by following the incorporation of a fluorescent phospholipid analogue into intracytoplasmic inclusion bodies characteristic of phospholipid storage disorders. At 24 and 48 hr, none of the parent compounds induced phospholipidosis
in vitro in rat or human hepatocytes. Phospholipidosis was associated primarily with an amine metabolite of ABT-770. The amine metabolite of another MMPI, ABT-518 ([
S-(
R∗,
R∗)]-
N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]ethyl]-
N-hydroxyformamide), produced little phospholipidosis in rat and human hepatocytes even at concentrations up to 100 μM. The presence or absence of phospholipidosis in the
in vitro assay correlated well with ultrastructural findings and drug accumulation in rat tissues. ABT-770, which produced phospholipidosis associated with its amine metabolite
in vitro and
in vivo, also generated a higher tissue to plasma distribution of metabolites particularly in tissues where phospholipidosis was observed. ABT-518 and its amine metabolite, however, produced low tissue to plasma ratios and induced little to no phospholipidosis
in vitro or
in vivo. These results demonstrate that the phospholipidosis observed for ABT-770 could be attributed to a cationic metabolite, and that altering the properties of such a metabolite, by modification of the parent compound, alleviated the disorder.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/S0006-2952(01)00823-1</identifier><identifier>PMID: 11755120</identifier><identifier>CODEN: BCPCA6</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Animals ; Biological and medical sciences ; Biphenyl Compounds - adverse effects ; Biphenyl Compounds - metabolism ; Errors of metabolism ; Formamides - metabolism ; Formamides - pharmacology ; Hepatocytes ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; HIV Protease Inhibitors - adverse effects ; HIV Protease Inhibitors - metabolism ; Human ; Humans ; Hydroxamic Acids - adverse effects ; Hydroxamic Acids - metabolism ; Lipidoses - chemically induced ; Lipids (lysosomal enzyme disorders, storage diseases) ; Male ; Matrix metalloproteinase (MMP) ; Matrix Metalloproteinase Inhibitors ; Matrix Metalloproteinases - metabolism ; Medical sciences ; Metabolic diseases ; Metabolism ; Phospholipidosis ; Rat ; Rats ; Rats, Sprague-Dawley</subject><ispartof>Biochemical pharmacology, 2001-12, Vol.62 (12), p.1661-1673</ispartof><rights>2001 Elsevier Science Inc.</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0006-2952(01)00823-1$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13418363$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11755120$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gum, Rebecca J.</creatorcontrib><creatorcontrib>Hickman, Dean</creatorcontrib><creatorcontrib>Fagerland, Jane A.</creatorcontrib><creatorcontrib>Heindel, Matthew A.</creatorcontrib><creatorcontrib>Gagne, Gerard D.</creatorcontrib><creatorcontrib>Schmidt, James M.</creatorcontrib><creatorcontrib>Michaelides, Michael R.</creatorcontrib><creatorcontrib>Davidsen, Steven K.</creatorcontrib><creatorcontrib>Ulrich, Roger G.</creatorcontrib><title>Analysis of two matrix metalloproteinase inhibitors and their metabolites for induction of phospholipidosis in rat and human hepatocytes</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>ABT-770 [(
S)-
N-[1-[[4′-trifluoromethoxy-[1,1′-biphenyl]-4-yl]oxy]methyl-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-
N-hydroxyformamide], a matrix metalloproteinase inhibitor (MMPI), produced generalized phospholipidosis in rats. Phospholipid accumulation was accompanied by retention of drug-related material and was associated with increased mortality. Generation of a successful drug candidate depended upon understanding the cause of the phospholipidosis and redesigning the chemical structure accordingly. ABT-770 and other MMPIs, plus several metabolites of each, were assayed for their ability to induce phospholipidosis in primary cultured rat and human hepatocytes. Phospholipid accumulation was detected by following the incorporation of a fluorescent phospholipid analogue into intracytoplasmic inclusion bodies characteristic of phospholipid storage disorders. At 24 and 48 hr, none of the parent compounds induced phospholipidosis
in vitro in rat or human hepatocytes. Phospholipidosis was associated primarily with an amine metabolite of ABT-770. The amine metabolite of another MMPI, ABT-518 ([
S-(
R∗,
R∗)]-
N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]ethyl]-
N-hydroxyformamide), produced little phospholipidosis in rat and human hepatocytes even at concentrations up to 100 μM. The presence or absence of phospholipidosis in the
in vitro assay correlated well with ultrastructural findings and drug accumulation in rat tissues. ABT-770, which produced phospholipidosis associated with its amine metabolite
in vitro and
in vivo, also generated a higher tissue to plasma distribution of metabolites particularly in tissues where phospholipidosis was observed. ABT-518 and its amine metabolite, however, produced low tissue to plasma ratios and induced little to no phospholipidosis
in vitro or
in vivo. These results demonstrate that the phospholipidosis observed for ABT-770 could be attributed to a cationic metabolite, and that altering the properties of such a metabolite, by modification of the parent compound, alleviated the disorder.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biphenyl Compounds - adverse effects</subject><subject>Biphenyl Compounds - metabolism</subject><subject>Errors of metabolism</subject><subject>Formamides - metabolism</subject><subject>Formamides - pharmacology</subject><subject>Hepatocytes</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - metabolism</subject><subject>HIV Protease Inhibitors - adverse effects</subject><subject>HIV Protease Inhibitors - metabolism</subject><subject>Human</subject><subject>Humans</subject><subject>Hydroxamic Acids - adverse effects</subject><subject>Hydroxamic Acids - metabolism</subject><subject>Lipidoses - chemically induced</subject><subject>Lipids (lysosomal enzyme disorders, storage diseases)</subject><subject>Male</subject><subject>Matrix metalloproteinase (MMP)</subject><subject>Matrix Metalloproteinase Inhibitors</subject><subject>Matrix Metalloproteinases - metabolism</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Metabolism</subject><subject>Phospholipidosis</subject><subject>Rat</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkc2KFTEQhYMoznX0EZRsBF205qfTnV7JMPgHAy7UdahO0nRJd9IkuTr3DXxs03dGXRRFhe-cCnUIec7ZG8549_YrY6xrxKDEK8ZfM6aFbPgDcuC6l_W50w_J4R9yQZ7k_GMfdccfkwvOe6W4YAfy-yrAcsqYaZxo-RXpCiXhLV19gWWJW4rFY4DsKYYZRywxZQrB0TJ7TGdsjAsWn-kUU4Xc0RaMYbfb5phrLbihi_sKDDRBOcvn4wqBzn6DEu2pyp-SRxMs2T-775fk-4f3364_NTdfPn6-vrppvOS6NJwJC1y2wAblmAIvnHX90E8gtFXt2IMQnRvUoLRmXrVSjDCODICNVTe18pK8uPPdjuPqndkSrpBO5u9JKvDyHoBsYZkSBIv5PydbrmUnK_fujvP1tz_RJ5Mt-mC9w-RtMS6i4czsYZlzWGZPwjBuzmFVoz_Z3Ykh</recordid><startdate>20011215</startdate><enddate>20011215</enddate><creator>Gum, Rebecca J.</creator><creator>Hickman, Dean</creator><creator>Fagerland, Jane A.</creator><creator>Heindel, Matthew A.</creator><creator>Gagne, Gerard D.</creator><creator>Schmidt, James M.</creator><creator>Michaelides, Michael R.</creator><creator>Davidsen, Steven K.</creator><creator>Ulrich, Roger G.</creator><general>Elsevier Inc</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20011215</creationdate><title>Analysis of two matrix metalloproteinase inhibitors and their metabolites for induction of phospholipidosis in rat and human hepatocytes</title><author>Gum, Rebecca J. ; Hickman, Dean ; Fagerland, Jane A. ; Heindel, Matthew A. ; Gagne, Gerard D. ; Schmidt, James M. ; Michaelides, Michael R. ; Davidsen, Steven K. ; Ulrich, Roger G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-e318t-102ca134a095d05ae2dcd797fa28c54b7a226d9595880e5432babb0aa0bca1f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biphenyl Compounds - adverse effects</topic><topic>Biphenyl Compounds - metabolism</topic><topic>Errors of metabolism</topic><topic>Formamides - metabolism</topic><topic>Formamides - pharmacology</topic><topic>Hepatocytes</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - metabolism</topic><topic>HIV Protease Inhibitors - adverse effects</topic><topic>HIV Protease Inhibitors - metabolism</topic><topic>Human</topic><topic>Humans</topic><topic>Hydroxamic Acids - adverse effects</topic><topic>Hydroxamic Acids - metabolism</topic><topic>Lipidoses - chemically induced</topic><topic>Lipids (lysosomal enzyme disorders, storage diseases)</topic><topic>Male</topic><topic>Matrix metalloproteinase (MMP)</topic><topic>Matrix Metalloproteinase Inhibitors</topic><topic>Matrix Metalloproteinases - metabolism</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Metabolism</topic><topic>Phospholipidosis</topic><topic>Rat</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gum, Rebecca J.</creatorcontrib><creatorcontrib>Hickman, Dean</creatorcontrib><creatorcontrib>Fagerland, Jane A.</creatorcontrib><creatorcontrib>Heindel, Matthew A.</creatorcontrib><creatorcontrib>Gagne, Gerard D.</creatorcontrib><creatorcontrib>Schmidt, James M.</creatorcontrib><creatorcontrib>Michaelides, Michael R.</creatorcontrib><creatorcontrib>Davidsen, Steven K.</creatorcontrib><creatorcontrib>Ulrich, Roger G.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gum, Rebecca J.</au><au>Hickman, Dean</au><au>Fagerland, Jane A.</au><au>Heindel, Matthew A.</au><au>Gagne, Gerard D.</au><au>Schmidt, James M.</au><au>Michaelides, Michael R.</au><au>Davidsen, Steven K.</au><au>Ulrich, Roger G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analysis of two matrix metalloproteinase inhibitors and their metabolites for induction of phospholipidosis in rat and human hepatocytes</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2001-12-15</date><risdate>2001</risdate><volume>62</volume><issue>12</issue><spage>1661</spage><epage>1673</epage><pages>1661-1673</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><coden>BCPCA6</coden><abstract>ABT-770 [(
S)-
N-[1-[[4′-trifluoromethoxy-[1,1′-biphenyl]-4-yl]oxy]methyl-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-
N-hydroxyformamide], a matrix metalloproteinase inhibitor (MMPI), produced generalized phospholipidosis in rats. Phospholipid accumulation was accompanied by retention of drug-related material and was associated with increased mortality. Generation of a successful drug candidate depended upon understanding the cause of the phospholipidosis and redesigning the chemical structure accordingly. ABT-770 and other MMPIs, plus several metabolites of each, were assayed for their ability to induce phospholipidosis in primary cultured rat and human hepatocytes. Phospholipid accumulation was detected by following the incorporation of a fluorescent phospholipid analogue into intracytoplasmic inclusion bodies characteristic of phospholipid storage disorders. At 24 and 48 hr, none of the parent compounds induced phospholipidosis
in vitro in rat or human hepatocytes. Phospholipidosis was associated primarily with an amine metabolite of ABT-770. The amine metabolite of another MMPI, ABT-518 ([
S-(
R∗,
R∗)]-
N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]ethyl]-
N-hydroxyformamide), produced little phospholipidosis in rat and human hepatocytes even at concentrations up to 100 μM. The presence or absence of phospholipidosis in the
in vitro assay correlated well with ultrastructural findings and drug accumulation in rat tissues. ABT-770, which produced phospholipidosis associated with its amine metabolite
in vitro and
in vivo, also generated a higher tissue to plasma distribution of metabolites particularly in tissues where phospholipidosis was observed. ABT-518 and its amine metabolite, however, produced low tissue to plasma ratios and induced little to no phospholipidosis
in vitro or
in vivo. These results demonstrate that the phospholipidosis observed for ABT-770 could be attributed to a cationic metabolite, and that altering the properties of such a metabolite, by modification of the parent compound, alleviated the disorder.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>11755120</pmid><doi>10.1016/S0006-2952(01)00823-1</doi><tpages>13</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Biochemical pharmacology, 2001-12, Vol.62 (12), p.1661-1673 |
| issn | 0006-2952 1873-2968 |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Animals Biological and medical sciences Biphenyl Compounds - adverse effects Biphenyl Compounds - metabolism Errors of metabolism Formamides - metabolism Formamides - pharmacology Hepatocytes Hepatocytes - drug effects Hepatocytes - metabolism HIV Protease Inhibitors - adverse effects HIV Protease Inhibitors - metabolism Human Humans Hydroxamic Acids - adverse effects Hydroxamic Acids - metabolism Lipidoses - chemically induced Lipids (lysosomal enzyme disorders, storage diseases) Male Matrix metalloproteinase (MMP) Matrix Metalloproteinase Inhibitors Matrix Metalloproteinases - metabolism Medical sciences Metabolic diseases Metabolism Phospholipidosis Rat Rats Rats, Sprague-Dawley |
| title | Analysis of two matrix metalloproteinase inhibitors and their metabolites for induction of phospholipidosis in rat and human hepatocytes |
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