Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants.
Previously we reported a gene expression signature in rat liver for detecting a specific type of oxidative stress (OS) related to reactive metabolites (RM). High doses of the drugs disulfiram, ethinyl estradiol and nimesulide were used with another dozen paradigm OS/RM compounds, and three other drugs flutamide, phenacetin and sulindac were identified by this signature. In a second study, antiepileptic drugs were compared for covalent binding and their effects on OS/RM; felbamate, carbamazepine, and phenobarbital produced robust OS/RM gene expression. In the present study, liver RNA samples from drug-treated rats from more recent experiments were examined for statistical fit to the OS/RM signature. Of all 97 drugs examined, in addition to the nine drugs noted above, 19 more were identified as OS/RM-producing compounds-chlorpromazine, clozapine, cyproterone acetate, dantrolene, dipyridamole, glibenclamide, isoniazid, ketoconazole, methapyrilene, naltrexone, nifedipine, sulfamethoxazole, tamoxifen, coumarin, ritonavir, amitriptyline, valproic acid, enalapril, and chloramphenicol. Importantly, all of the OS/RM drugs listed above have been linked to idiosyncratic hepatotoxicity, excepting chloramphenicol, which does not have a package label for hepatotoxicity, but does have a black box warning for idiosyncratic bone marrow suppression. Most of these drugs are not acutely toxic in the rat. The OS/RM signature should be useful to avoid idiosyncratic hepatotoxicity of drug candidates.
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
Angelique
A
Leone
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
Alex
A
Nie
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
J
J
Brandon Parker
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
Sharmilee
S
Sawant
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
Leigh-Anne
LA
Piechta
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA. Electronic address: mkelley2@its.jnj.com.
Michael F
MF
Kelley
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
L
L
Mark Kao
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
S
S
Jim Proctor
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
Geert
G
Verheyen
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
Mark D
MD
Johnson
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
Peter G
PG
Lord
Preclinical Development & Safety, Janssen Pharmaceutical Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
Michael K
MK
McMillian
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005819:Genetic Markers; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043922:Toxicogenetics / Q000379:methods*
D005819:Genetic Markers
Adverse drug reactions; DILI; Drug induced liver injury; Idiosyncratic hepatotoxicity; Oxidative stress; Reactive metabolites