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Development of Hibernomas in Rats Dosed with Phentolamine Mesylate During the 24-Month Carcinogenicity Study

Schering-Plough Research Institute, Lafayette, New Jersey 07848, frederique.poulet{at}spcorp.com

Mark R. Berardi

Schering-Plough Research Institute, Lafayette, New Jersey 07848

William Halliwell

Schering-Plough Research Institute, Lafayette, New Jersey 07848

Barbara Hartman

Schering-Plough Research Institute, Lafayette, New Jersey 07848

Carol Auletta

Huntingdon Life Sciences, East Millstone, New Jersey 08875

Henry Bolte

Huntingdon Life Sciences, East Millstone, New Jersey 08875

Phentolamine is a reversible competitive -adrenergic antagonist with similar affinities for 1 and 2 receptors. It has a long history of safe clinical use, and was developed as a potential therapy for male erectile dysfunction because of its capacity to increase the arteriolar blood flow to the corpora cavernosa. Phentolamine mesylate was administered to rats by oral gavage at daily doses of 10, 50, and 150 mg/kg for 24 months. A dose-related increase in mortality, ascribed to an exaggerated pharmacologic effect, was seen at high doses. Systemic exposure as measured by plasma drug concentration increased with dose and duration of dosing and slight drug accumulation occurred, particularly in high-dose males. In the treated groups, 10 males and 1 female were diagnosed with hibernomas, neoplasms of brown adipose tissue, which appeared in the thoracic cavity or retroperitoneal area as circumscribed, tan to reddish-brown lobulated masses. Histologically, the masses were well circumscribed with variably sized lobules defined by a rich capillary network and consisted of closely apposed oval to polygonal cells with large amounts of cytoplasm and a centrally located nucleus. The cytoplasm's appearance varied from multivacuolated to univacuolated to granular eosinophilic. In a few cases, neoplastic emboli were observed in capsular vessels. Ultrastructurally, the neoplastic cells contained numerous mitochondria with transverse parallel cristae that occupied over 60% of the cytoplasm and lipid droplets. This study documents the previously unreported development of hibernomas in rats treated with phentolamine mesylate.

Key Words: Hibernoma • brown fat • rat • carcinogenicity • phentolamine.

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