title: Characterization of xenobiotic-induced hepatocellular enzyme induction in rats: anticipated thyroid effects and unique pituitary gland findings.
abstract: During routine safety evaluation of RO2910, a non-nucleoside reverse transcriptase inhibitor for HIV infection, histopathology findings concurrent with robust hepatocellular induction occurred in multiple organs, including a unique, albeit related, finding in the pituitary gland. For fourteen days, male and female rats were administered, by oral gavage vehicle, 100, 300, or 1000 mg/kg/day of RO2910. Treated groups had elevated serum thyroid-stimulating hormone and decreased total thyroxine, and hypertrophy in the liver, thyroid gland, and pituitary pars distalis. These were considered consequences of hepatocellular induction and often were dose dependent and more pronounced in males than in females. Hepatocellular centrilobular hypertrophy corresponded with increased expression of cytochrome P450s 2B1/2, 3A1, and 3A2 and UGT 2B1. Bilateral thyroid follicular cell hypertrophy occurred concurrent to increased mitotic activity and sometimes colloid depletion, which were attributed to changes in thyroid hormone levels. Males had hypertrophy of thyroid-stimulating hormone-producing cells (thyrotrophs) in the pituitary pars distalis. All findings were consistent with the well-established adaptive physiologic response of rodents to xenobiotic-induced hepatocellular microsomal enzyme induction. Although the effects on the pituitary gland following hepatic enzyme induction-mediated hypothyroidism have not been reported previously, other models of stress and thyroid depletion leading to pituitary stimulation support such a shared pathogenesis.
authors.affiliation: Roche Pharmaceuticals, Nonclinical Safety, Nutley, New Jersey 07110, USA. tanja.zabka@roche.com
authors.forename: Tanja S
authors.initials: TS
authors.lastname: Zabka
authors.forename: Mark R
authors.initials: MR
authors.lastname: Fielden
authors.forename: Rosario
authors.initials: R
authors.lastname: Garrido
authors.forename: Jianhua
authors.initials: J
authors.lastname: Tao
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Fretland
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Fretland
authors.forename: Mudher A
authors.initials: MA
authors.lastname: Albassam
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Kolaja
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006706:Homeostasis / Q000187:drug effects; D007028:Hypothalamic Hormones / Q000097:blood; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008938:Mitosis / Q000187:drug effects; D010902:Pituitary Gland / Q000187:drug effects* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000378:metabolism; D012737:Sex Factors; D013961:Thyroid Gland / Q000187:drug effects* / Q000473:pathology; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D015262:Xenobiotics / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D007028:Hypothalamic Hormones; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; D015262:Xenobiotics; D013972:Thyrotropin; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D013974:Thyroxine