Vascular effects of GI262570X (PPAR-gamma agonist) in the brown adipose tissue of Han Wistar rats: a review of 1-month, 13-week, 27-week and 2-year oral toxicity studies.
We describe and discuss microscopic findings in the brown adipose tissue (BAT) blood vessels of Han Wistar rats treated with GI262570X, a peroxisome proliferator-activated receptor-gamma agonist (PPAR-gamma agonist) by oral gavage for 28 days, 13 weeks, 27 weeks, and 2 years. Review of these studies revealed a consistent vascular change, consisting of multifocal fatty infiltration in the BAT of treated rats. A similar vascular change was not seen in other vessels or organs. Microscopically, fatty infiltration was characterized primarily by round, clear vacuoles within the tunica media and/or tunica adventitia of small and medium-sized arteries and arterioles. Occasionally, these vacuoles had peripherally located nuclei and morphologically resembled adipocytes, suggesting a well-characterized PPAR effect (ie, differentiation of stem cells or preadipocytes into mature adipocytes). However, administration of GI262570X up to 2 years failed to induce more severe or progressive lesions in the blood vessels of rat BAT and, in particular, did not result in induction of any atherosclerotic-like lesions or foam cell infiltration. At the longer exposure, there was an apparent reduction of severity and/or incidence, indicating a possible adaptive response. These results suggest that the possibility of generating atherosclerotic-like lesions through prolonged treatment of GI262570X (PPAR-gamma agonist) is highly unlikely in rats.
Department of Pathology, GlaxoSmithKline Inc, Research Triangle Park, North Carolina 27709, USA. cse63957@gsk.com
Chandikumar S
CS
Elangbam
Thomas A
TA
Brodie
H Roger
HR
Brown
James B
JB
Nold
Timothy J
TJ
Raczniak
Ronald D
RD
Tyler
Ruth M
RM
Lightfoot
Henry G
HG
Wall
D002001:Adipose Tissue, Brown / Q000098:blood supply / Q000187:drug effects*; D000818:Animals; D001161:Arteriosclerosis / Q000139:chemically induced; D002455:Cell Division / Q000187:drug effects; D005260:Female; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D010080:Oxazoles; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives
D007004:Hypoglycemic Agents; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C422415:farglitazar; D014443:Tyrosine