Human & Experimental Toxicology

 

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Human & Experimental Toxicology, Vol. 24, No. 12, 643-654 (2005)
DOI: 10.1191/0960327105ht568oa

Increase in thyroid follicular cell tumors in nelfinavir-treated rats observed in a 2-year carcinogenicity study is consistent with a rat-specific mechanism of thyroid neoplasia

L A Burns-Naas

Worldwide Safety Sciences, Pfizer Global Research and Development, 10777 Science Center Drive, San Diego, CA 92121, USAleighann.burns{at}pfizer.com

M Zorbas

B Jessen

W Evering

G Stevens

Pfizer Global Research and Development, San Diego, CA 92121, USA

J L Ivett

Covance Laboratories, Inc., Vienna, VA 22182, USA

T E Ryan

Covance Laboratories, Inc., Madison, WI 53704, USA

J C Cook

Pfizer Global Research and Development, Groton, CT 06340, USA

C C Capen

The Ohio State University, Columbus, OH 43210, USA

M Chen

Pfizer Global Research and Development, San Diego, CA 92121, USA; Novartis Genomics Institute, San Diego, CA, USA

G Furman

Pfizer Global Research and Development, San Diego, CA 92121, USA

J C Theiss

Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA; Sun Coast Tox, San Diego, CA, USA

S Webber

Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA; Stephanie Webber Consulting, San Diego, CA, USA

E Wu

B Shetty

Pfizer Global Research and Development, San Diego, CA 92121, USA

R Gasser

Hoffmann-La Roche AG, 4070 Basel, Switzerland

R M McClain

McClain Associates, Randolph, NJ 07869, USA

The carcinogenic potential of nelfinavir mesylate (nelfinavir) was evaluated in a 2-year oral (gavage) study on Sprague-Dawley rats at dose levels of 0 (control), 0 (vehicle control), 100, 300 and 1000 mg/kg per day. At the end of the treatment, increased incidences of thyroid follicular cell hyperplasia and neoplasms were observed at 300 (males) and 1000 mg/kg per day (both sexes). There were no other treatment-related effects and no tumors at other sites. Results from previous studies indicated a number of effects in the liver and thyroid, as well as metabolic profiles that suggested nelfinavir might cause thyroid hyperplasia/neoplasia secondary to hormone imbalance by altering thyroid hormone disposition. To investigate this hypothesis, the effects of nelfinavir on gene expression in rat hepatocytes and liver slices (in vitro), thyroxine plasma clearance, and thyroid gland function were evaluated. Compared to controls, gene expression analyses demonstrated an increased expression of glucuronyltransferase (UDPGT) and CYP450 3A1 in nelfinavir-treated rat hepatocytes and liver slices. In rats treated with nelfinavir (1000 mg/kg per day) for 4 weeks, liver weights and centrilobular hepatocellular hypertrophy were increased and minimal to mild diffuse thyroid follicular cell hypertrophy and follicular cell hyperplasia were evident in the thyroid gland. Thyroid-stimulating hormone (TSH) levels were significantly increased (three-fold), while tri-iodothyronine (T3)/tetraiodothyronine (T4) and reverse T3(rT3) levels were unchanged, indicating that a compensated state to maintain homeostasis of T3/T4 had been achieved. Plasma 125I-thyroxine clearance was increased and the plasma thyroxine AUC0 48 was decreased (24%) compared to control. In conclusion, these data indicate that thyroid neoplasms observed in the nelfinavir-treated rats were secondary to thyroid hormone imbalance. Increased thyroxine clearance contributes to the effects of nelfinavir on thyroid gland function and is probably a result of UDPGT induction that leads to elevated TSH levels in the rat and eventual thyroid neoplasia. These results are consistent with a well-recognized rat-specific mechanism for thyroid neoplasms.

Key Words: antiviral • carcinogenicity • HIV • nelfinavir • T3 • T4 • thyroid gland function • thyroid hormone • thyroxine


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