Reactive metabolites(RMs) generated by hepatic metabolism are thought to play an important role in the pathogenesis of drug-induced liver injury(DILI). Like many synthetic drugs undergoing metabolic activation to form...Reactive metabolites(RMs) generated by hepatic metabolism are thought to play an important role in the pathogenesis of drug-induced liver injury(DILI). Like many synthetic drugs undergoing metabolic activation to form RMs which are often associated with drug toxicity, it is recognized that some herbal components may be also converted to toxic, or even mutagenetic and carcinogenic metabolites by cytochrome P450 s(CYP450 s). This review focuses on the metabolic activation of herbal components and its liver toxicological implications. By summarizing references, we found that hepatotoxic herbal components via producing RMs have some certain structural dependence. There is a correlation between the generation of RMs and the structures, which provides a good chance for the early discovery of toxic ingredients in Traditional Chinese medicines(TCMs): i) A potential hepatotoxic component information database based on active functional groups can be built, which might provide an early information for the basic research of hepatotoxic substances in TCMs;ii) RMs can combine with CYP450 s to form a complete antigen, which eventually leads to an antigen-specific immune response. RMs-CYP450 protein complete antigen can be set up, and the potential idiosyncratic liver toxicity might be predicted by testing RMs-CYP450 protein antibody in plasma.展开更多
Idiosyncratic hepatotoxicity accounts for many drug failures in the clinic and is a leading cause for black-boxed and withdrawn drugs. This toxicity has proven difficult to predict preclinically, but correlates with o...Idiosyncratic hepatotoxicity accounts for many drug failures in the clinic and is a leading cause for black-boxed and withdrawn drugs. This toxicity has proven difficult to predict preclinically, but correlates with oxidative stress/reactive metabolites (OS/RM). As noted previously for antiepileptic compounds, many drugs causing idiosyncratic adverse drug effects are detected by OS/RM gene expression responses in the rat. In the present study, two immune activation models, low dose lipopolysaccharide (1 mg/kg IV) and 5% dextran sulphate sodium (DSS) in drinking water, were examined to determine if either would convert the non-toxic idiosyncratic toxicant carbamazepine (225 mg/kg) into a rat hepatotoxicant at 24 hours. Using the low dose LPS model, about 1/3 of the carbamazepine-treated rats either showed robust ALT and AST elevations with histopathological evidence of hepatotoxicity, or died. Rats in this LPS/carbamazepine group were subdivided based on ALT values into non-responders, responders or robust responders. Whereas most carbamazepine-induced mRNAs were repressed by LPS across all rats in this group, the OS/ RM genes aflatoxin aldehyde reductase (Afar) and glutathione transferase Ya (Gstya) were repressed only in the robust responder subgroup;it is unclear whether repression of these genes contributes to or results from hepatotoxicity. The OS/RM gene microsomal epoxide hydrolase (mEphx) showed repression across all rats. NAD(P)H: menadione oxidoreductase (Nmor) is an OS/RM-responsive gene that is also induced by LPS, confounding interpretation of its changes. After pretreatment with 5% DSS at 24 hours or for 5 days, using a protocol that reportedly produces increased endotoxin absorption, carbamazepine was not converted to a hepatototoxicant in any rats. Instead, DSS produced a pronounced (2- to 6-fold) and selective potentiation of carbamazepine induction of OS/RM-responsive mRNAs. The lack of repressive effects of DSS on these mRNAs or in converting carbamazepine to a hepatotoxicant was not due to dese展开更多
Background: The aims of this study were(a) to ascertain age-related changes in the reference values in hematological and serum biochemical examinations of beagles,and(b) to clarify the changes in these findings, inclu...Background: The aims of this study were(a) to ascertain age-related changes in the reference values in hematological and serum biochemical examinations of beagles,and(b) to clarify the changes in these findings, including acute phase proteins and oxidative stress, throughout pregnancy and after parturition.Methods: Clinicopathological parameters were measured in young beagles at 6, 9 and 12 months and in adult beagles aged from 24 to 60 months. Likewise, pregnant beagles were investigated throughout the pregnancy and after parturition.Results: Apparent age-related changes were found in erythrocytic parameters during the growth and development of beagles. Most of the parameters(total protein,albumin, blood urea nitrogen, creatinine, urate, alkaline phosphatase(ALP) and creatine kinase(CK) exhibited age-dependent transitions. White cell count significantly increased after 30 days of pregnancy. The values of erythrocytic parameters moderately decreased during the second half of the pregnancy. Triglycerides, total cholesterol, free cholesterol and phospholipid concentrations increased in the mid- and late stages of pregnancy. ALP, lactate dehydrogenase, CK and cholinesterase activities markedly increased during pregnancy and/or after parturition. C-reactive protein(CRP) concentrations gradually increased and reached a maximum after 30-40 days of pregnancy. Serum amyloid A(SAA) levels markedly increased at 30 days of pregnancy before subsiding, and then increased again 3 days after parturition. Reactive oxygen metabolites(d-ROMs) showed significant increases after 30 and 40 days of pregnancy.Conclusions: Reference values for hematological and serum biochemical examinations should be used for health evaluation of dogs, taking sex, age and the stage of pregnancy into consideration. Measurements of CRP, SAA and d-ROM levels are also useful for assessing maternal conditions in mid-pregnancy.展开更多
基金supported by Scientific Research Project of Tianjin Municipal Education Commission (No. 2017KJ135)the Key Projects of Tianjin Science and Technology Support Program (No. 16YFZCSY00440)the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT, No. IRT_14R41)
文摘Reactive metabolites(RMs) generated by hepatic metabolism are thought to play an important role in the pathogenesis of drug-induced liver injury(DILI). Like many synthetic drugs undergoing metabolic activation to form RMs which are often associated with drug toxicity, it is recognized that some herbal components may be also converted to toxic, or even mutagenetic and carcinogenic metabolites by cytochrome P450 s(CYP450 s). This review focuses on the metabolic activation of herbal components and its liver toxicological implications. By summarizing references, we found that hepatotoxic herbal components via producing RMs have some certain structural dependence. There is a correlation between the generation of RMs and the structures, which provides a good chance for the early discovery of toxic ingredients in Traditional Chinese medicines(TCMs): i) A potential hepatotoxic component information database based on active functional groups can be built, which might provide an early information for the basic research of hepatotoxic substances in TCMs;ii) RMs can combine with CYP450 s to form a complete antigen, which eventually leads to an antigen-specific immune response. RMs-CYP450 protein complete antigen can be set up, and the potential idiosyncratic liver toxicity might be predicted by testing RMs-CYP450 protein antibody in plasma.
文摘Idiosyncratic hepatotoxicity accounts for many drug failures in the clinic and is a leading cause for black-boxed and withdrawn drugs. This toxicity has proven difficult to predict preclinically, but correlates with oxidative stress/reactive metabolites (OS/RM). As noted previously for antiepileptic compounds, many drugs causing idiosyncratic adverse drug effects are detected by OS/RM gene expression responses in the rat. In the present study, two immune activation models, low dose lipopolysaccharide (1 mg/kg IV) and 5% dextran sulphate sodium (DSS) in drinking water, were examined to determine if either would convert the non-toxic idiosyncratic toxicant carbamazepine (225 mg/kg) into a rat hepatotoxicant at 24 hours. Using the low dose LPS model, about 1/3 of the carbamazepine-treated rats either showed robust ALT and AST elevations with histopathological evidence of hepatotoxicity, or died. Rats in this LPS/carbamazepine group were subdivided based on ALT values into non-responders, responders or robust responders. Whereas most carbamazepine-induced mRNAs were repressed by LPS across all rats in this group, the OS/ RM genes aflatoxin aldehyde reductase (Afar) and glutathione transferase Ya (Gstya) were repressed only in the robust responder subgroup;it is unclear whether repression of these genes contributes to or results from hepatotoxicity. The OS/RM gene microsomal epoxide hydrolase (mEphx) showed repression across all rats. NAD(P)H: menadione oxidoreductase (Nmor) is an OS/RM-responsive gene that is also induced by LPS, confounding interpretation of its changes. After pretreatment with 5% DSS at 24 hours or for 5 days, using a protocol that reportedly produces increased endotoxin absorption, carbamazepine was not converted to a hepatototoxicant in any rats. Instead, DSS produced a pronounced (2- to 6-fold) and selective potentiation of carbamazepine induction of OS/RM-responsive mRNAs. The lack of repressive effects of DSS on these mRNAs or in converting carbamazepine to a hepatotoxicant was not due to dese
文摘Background: The aims of this study were(a) to ascertain age-related changes in the reference values in hematological and serum biochemical examinations of beagles,and(b) to clarify the changes in these findings, including acute phase proteins and oxidative stress, throughout pregnancy and after parturition.Methods: Clinicopathological parameters were measured in young beagles at 6, 9 and 12 months and in adult beagles aged from 24 to 60 months. Likewise, pregnant beagles were investigated throughout the pregnancy and after parturition.Results: Apparent age-related changes were found in erythrocytic parameters during the growth and development of beagles. Most of the parameters(total protein,albumin, blood urea nitrogen, creatinine, urate, alkaline phosphatase(ALP) and creatine kinase(CK) exhibited age-dependent transitions. White cell count significantly increased after 30 days of pregnancy. The values of erythrocytic parameters moderately decreased during the second half of the pregnancy. Triglycerides, total cholesterol, free cholesterol and phospholipid concentrations increased in the mid- and late stages of pregnancy. ALP, lactate dehydrogenase, CK and cholinesterase activities markedly increased during pregnancy and/or after parturition. C-reactive protein(CRP) concentrations gradually increased and reached a maximum after 30-40 days of pregnancy. Serum amyloid A(SAA) levels markedly increased at 30 days of pregnancy before subsiding, and then increased again 3 days after parturition. Reactive oxygen metabolites(d-ROMs) showed significant increases after 30 and 40 days of pregnancy.Conclusions: Reference values for hematological and serum biochemical examinations should be used for health evaluation of dogs, taking sex, age and the stage of pregnancy into consideration. Measurements of CRP, SAA and d-ROM levels are also useful for assessing maternal conditions in mid-pregnancy.
