title: MEK and ERK Kinase Inhibitors Increase Circulating Ceruloplasmin and Cause Green Serum in Rats.
abstract: Inhibition of the mitogen-activated protein kinase/extracellular signal-regulated (MAPK/ERK) pathway is an attractive therapeutic approach for human cancer therapy. In the course of evaluating structurally distinct small molecule inhibitors that target mitogen-activated protein kinase kinase (MEK) and ERK kinases in this pathway, we observed an unusual, dose-related increase in the incidence of green serum in preclinical safety studies in rats. Having ruled out changes in bilirubin metabolism, we demonstrated a 2- to 3-fold increase in serum ceruloplasmin levels, likely accounting for the observed green color. This was not associated with an increase in α-2-macroglobulin, the major acute phase protein in rats, indicating that ceruloplasmin levels increased independently of an inflammatory response. Elevated serum ceruloplasmin was also not correlated with changes in total hepatic copper, adverse clinical signs, or pathology findings indicative of copper toxicity, therefore discounting copper overload as the etiology. Both ERK and MEK inhibitors led to increased ceruloplasmin secretion in rat primary hepatocyte cultures in vitro, and this increase was associated with activation of the Forkhead box, class O1 (FOXO1) transcription factor. In conclusion, increased serum ceruloplasmin induced by MEK and ERK inhibition is due to increased synthesis by hepatocytes from FOXO1 activation and results in the nonadverse development of green serum in rats.
authors: 1 Genentech, Inc., South San Francisco, California, USA.
authors: Dolores
authors: D
authors: Diaz
authors: 1 Genentech, Inc., South San Francisco, California, USA.|2 Medivation, San Francisco, California, USA.
authors: Rama
authors: R
authors: Pai
authors: 1 Genentech, Inc., South San Francisco, California, USA.
authors: Gary
authors: G
authors: Cain
authors: 1 Genentech, Inc., South San Francisco, California, USA.
authors: Nghi
authors: N
authors: La
authors: 1 Genentech, Inc., South San Francisco, California, USA.
authors: Donna
authors: D
authors: Dambach
authors: 1 Genentech, Inc., South San Francisco, California, USA.
authors: Jacob
authors: J
authors: Schwartz
authors: 1 Genentech, Inc., South San Francisco, California, USA.|3 Gilead Sciences, Foster City, California, USA.
authors: Jacqueline M
authors: JM
authors: Tarrant
mesh_terms: D000818:Animals; D001775:Blood Circulation; D002570:Ceruloplasmin / Q000032:analysis*; D003300:Copper / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D017207:Rats, Sprague-Dawley; D044967:Serum / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D003300:Copper; D002570:Ceruloplasmin
keywords: ERK; FOXO; MEK; ceruloplasmin; copper