Abstract:
:Lovastatin (LOVA) is a potent inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase widely used in clinical practice. We treated primary cultures of adult rat hepatocytes, maintained in a minimal, serum-free medium on Matrigel, a reconstituted basement membrane, with this drug, and found that the amounts of P450 2B2 mRNA detected on Northern blots were increased at the same doses (10(-5) to 3 x 10(-5) M) required for induction of HMG-CoA reductase mRNA, a gene known to be under oxysterol regulatory control. LOVA treatment produced selective effects increasing also the mRNA levels for P450s 2C6, 2C7, 3A1, and 4A1 but not for 1A1, 2A1/2, or NADPH-cytochrome P450 oxidoreductase. LOVA treatment increased the induction of 2B1/2 mRNA in cells cotreated with either phenobarbital (PB; 10(-4) M) or clotrimazole (CTZ; 10(-5) M), or of 3A1 mRNA in cells cotreated with PB (2 x 10(-3) M), but not dexamethasone (10(-5) M. LOVA treatment did not potentiate the induction of 1A1 or 4A1 mRNA in cells cotreated with beta-naphthoflavone (10(-5) M) or ciprofibrate (10(-4) M), respectively. In contrast to the potentiation of 2B1/2 mRNA induction produced by treatments with LOVA in combination with PB or CTZ, cotreatment of hepatocytes with PB and CTZ did not result in increased induction relative to that seen in cells treated with either agent alone. Treatment of hepatocyte cultures with either mevalonate (3 x 10(-4) to 3 x 10(-3) M), the immediate product of HMG-CoA reductase, or 25-hydroxycholesterol (10(-6) to 10(-5) M), a model oxysterol, resulted in dose-dependent suppression of 2B1/2 mRNA induction in cells treated with PB-like inducers. Taken together, our results demonstrate that LOVA is a unique inducer of P450 mRNA in cultured rat hepatocytes and implicate oxysterols as potential intracellular modulators of 2B1/2 induction. We conclude that endogenous metabolic factors including those related to cholesterol biosynthesis are critical in induction of liver cytochromes P450 2B1 and 2B2 by PB and "PB-like" agents.
journal_name
Toxicol Appl Pharmacoljournal_title
Toxicology and applied pharmacologyauthors
Kocarek TA,Schuetz EG,Guzelian PSdoi
10.1006/taap.1993.1115subject
Has Abstractpub_date
1993-06-01 00:00:00pages
298-307issue
2eissn
0041-008Xissn
1096-0333pii
S0041-008X(83)71115-4journal_volume
120pub_type
杂志文章abstract::Contact sensitization is caused by low molecular weight compounds which penetrate the skin and bind to protein. In many cases, these compounds are activated to reactive species, either by autoxidation on exposure to air or by metabolic activation in the skin. Geraniol, a widely used fragrance chemical, is considered t...
journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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doi:10.1016/j.taap.2004.12.018
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journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1999.8640
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
pub_type: 临床试验,杂志文章
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abstract::The utility of isolated rat hepatocytes as a model system for screening potential chelators in treatment of Cd intoxication was studied. The ability of the chelators diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 2,3-dimercaptosuccinic acid (DMSA), diethyldithiocarbamic acid (DDC), ...
journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
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