This chapter outlines the three commonly used in silico toxicology methodologies: statistical-bas... more This chapter outlines the three commonly used in silico toxicology methodologies: statistical-based (QSAR) models, expert rule-based, and read-across. A description is provided illustrating how these models are built and how they make predictions to help explain the strengths and limitations of the different methodologies since they may otherwise appear as a “black box”. Examples are provided of commercial and academic systems that can be used to make predictions. A case study will be presented to illustrate how all three methodologies can be used to support the prediction of mutagenicity. Finally, the chapter concludes with a discussion of some future directions.
Pharmacological activation of the constitutive androstane recep-tor (CAR) protects the liver duri... more Pharmacological activation of the constitutive androstane recep-tor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice before and during induction of intrahe-patic cholestasis using the secondary bile acid, lithocholic acid (LCA). In LCA-treated WT and all the CAR-null groups (excluding controls), histology revealed severe multifocal necrosis. This pa-thology was absent in WT mice pretreated with PB and TCPOBOP, indicating CAR-dependent hepatoprotection. Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and trihy-droxy bile acids in PB- and TCPOBOP-pretreated WT mice corre-
There are many causes of cholestasis, which results when the flow of bile acids is slowed or stop... more There are many causes of cholestasis, which results when the flow of bile acids is slowed or stopped. Bile acids are hydrophobic molecules synthesized from cholesterol in the liver, and when present in excess, are cytotoxic to cell membranes. Treatment options for cholestasis are limited, and if left untreated or inadequately treated, many patients will require a liver transplant; thus, underscoring the importance of successfully managing this disease. Activation of nuclear receptors in animal models has been shown to be hepatoprotective during bile acid-induced cholestasis; however, the mechanisms underlying the hepatoprotective effects are poorly understood. Therefore, the over-arching goal of this project is to glean an improved comprehension of the mechanisms of hepatoprotection during bile acid-induced cholestasis. All of the studies involve administration of CAR activators phenobarbital (PB), oltipraz (OPZ), 1,4-bis[2(3,5-dichloropyridyloxy)]benzene [TCPOBOP (TC)] or corn oil ...
This chapter outlines the three commonly used in silico toxicology methodologies: statistical-bas... more This chapter outlines the three commonly used in silico toxicology methodologies: statistical-based (QSAR) models, expert rule-based, and read-across. A description is provided illustrating how these models are built and how they make predictions to help explain the strengths and limitations of the different methodologies since they may otherwise appear as a “black box”. Examples are provided of commercial and academic systems that can be used to make predictions. A case study will be presented to illustrate how all three methodologies can be used to support the prediction of mutagenicity. Finally, the chapter concludes with a discussion of some future directions.
This chapter outlines the three commonly used in silico toxicology methodologies: statistical-bas... more This chapter outlines the three commonly used in silico toxicology methodologies: statistical-based (QSAR) models, expert rule-based, and read-across. A description is provided illustrating how these models are built and how they make predictions to help explain the strengths and limitations of the different methodologies since they may otherwise appear as a “black box”. Examples are provided of commercial and academic systems that can be used to make predictions. A case study will be presented to illustrate how all three methodologies can be used to support the prediction of mutagenicity. Finally, the chapter concludes with a discussion of some future directions.
Pharmacological activation of the constitutive androstane recep-tor (CAR) protects the liver duri... more Pharmacological activation of the constitutive androstane recep-tor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice before and during induction of intrahe-patic cholestasis using the secondary bile acid, lithocholic acid (LCA). In LCA-treated WT and all the CAR-null groups (excluding controls), histology revealed severe multifocal necrosis. This pa-thology was absent in WT mice pretreated with PB and TCPOBOP, indicating CAR-dependent hepatoprotection. Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and trihy-droxy bile acids in PB- and TCPOBOP-pretreated WT mice corre-
There are many causes of cholestasis, which results when the flow of bile acids is slowed or stop... more There are many causes of cholestasis, which results when the flow of bile acids is slowed or stopped. Bile acids are hydrophobic molecules synthesized from cholesterol in the liver, and when present in excess, are cytotoxic to cell membranes. Treatment options for cholestasis are limited, and if left untreated or inadequately treated, many patients will require a liver transplant; thus, underscoring the importance of successfully managing this disease. Activation of nuclear receptors in animal models has been shown to be hepatoprotective during bile acid-induced cholestasis; however, the mechanisms underlying the hepatoprotective effects are poorly understood. Therefore, the over-arching goal of this project is to glean an improved comprehension of the mechanisms of hepatoprotection during bile acid-induced cholestasis. All of the studies involve administration of CAR activators phenobarbital (PB), oltipraz (OPZ), 1,4-bis[2(3,5-dichloropyridyloxy)]benzene [TCPOBOP (TC)] or corn oil ...
This chapter outlines the three commonly used in silico toxicology methodologies: statistical-bas... more This chapter outlines the three commonly used in silico toxicology methodologies: statistical-based (QSAR) models, expert rule-based, and read-across. A description is provided illustrating how these models are built and how they make predictions to help explain the strengths and limitations of the different methodologies since they may otherwise appear as a “black box”. Examples are provided of commercial and academic systems that can be used to make predictions. A case study will be presented to illustrate how all three methodologies can be used to support the prediction of mutagenicity. Finally, the chapter concludes with a discussion of some future directions.
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