{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T05:57:38Z","timestamp":1781071058063,"version":"3.54.1"},"reference-count":36,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2005,12,1]],"date-time":"2005-12-01T00:00:00Z","timestamp":1133395200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hum Exp Toxicol"],"published-print":{"date-parts":[[2005,12]]},"abstract":"<jats:p>\n                    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 (T\n                    <jats:sub>3<\/jats:sub>\n                    )\/tetraiodothyronine (T\n                    <jats:sub>4<\/jats:sub>\n                    ) and reverse T\n                    <jats:sub>3<\/jats:sub>\n                    (rT\n                    <jats:sub>3<\/jats:sub>\n                    ) levels were unchanged, indicating that a compensated state to maintain homeostasis of T\n                    <jats:sub>3<\/jats:sub>\n                    \/T\n                    <jats:sub>4<\/jats:sub>\n                    had been achieved. Plasma\n                    <jats:sup>125<\/jats:sup>\n                    I-thyroxine clearance was increased and the plasma thyroxine AUC\n                    <jats:sub>0<\/jats:sub>\n                    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.\n                  <\/jats:p>","DOI":"10.1191\/0960327105ht568oa","type":"journal-article","created":{"date-parts":[[2005,11,26]],"date-time":"2005-11-26T19:19:32Z","timestamp":1133032772000},"page":"643-654","source":"Crossref","is-referenced-by-count":15,"title":["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"],"prefix":"10.1177","volume":"24","author":[{"given":"L A","family":"Burns-Naas","sequence":"first","affiliation":[{"name":"Worldwide Safety Sciences, Pfizer Global Research and Development, 10777                         Science Center Drive, San Diego, CA 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Zorbas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Jessen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W","family":"Evering","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Stevens","sequence":"additional","affiliation":[{"name":"Pfizer Global Research and Development, San Diego, CA 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J L","family":"Ivett","sequence":"additional","affiliation":[{"name":"Covance Laboratories, Inc., Vienna, VA 22182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T E","family":"Ryan","sequence":"additional","affiliation":[{"name":"Covance Laboratories, Inc., Madison, WI 53704, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J C","family":"Cook","sequence":"additional","affiliation":[{"name":"Pfizer Global Research and Development, Groton, CT 06340, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C C","family":"Capen","sequence":"additional","affiliation":[{"name":"The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Chen","sequence":"additional","affiliation":[{"name":"Pfizer Global Research and Development, San Diego, CA 92121, USA; 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