Studies on the mechanism of simvastatin-induced thyroid hypertrophy and follicular cell adenoma in the rat.
Female Sprague-Dawley rats were treated with either simvastatin (a novel competitive inhibitor of HMG CoA reductase) or phenobarbital (positive control) to ascertain the possible relationship between the effects of simvastatin on hepatic metabolism and the thyroid hypertrophy and follicular cell adenomas which it produces in this strain of rat. The test compounds were administered orally at doses of 100 mg/kg (divided doses at 50 mg/kg, b.i.d.). (This dose of simvastatin represents approximately 250 times the human dose.) After 5 weeks of treatment, either simvastatin or phenobarbital produced significant increases (35% and 39% above control, respectively) in serum thyroid stimulating hormone (TSH), a significant increase (39% and 120% above control, respectively) in the systemic clearance of 125I-thyroxine, and slight decreases in serum thyroxine levels. Statistically significant increases in liver and thyroid weights were associated with phenobarbital treatment. With simvastatin, increased liver weights occurred. At the microscopic level, thyroid hypertrophy was observed in all phenobarbital-treated rats and to a lesser degree in most simvastatin-treated animals. Simvastatin did not markedly alter liver microsomal enzyme activities with the exception of the anticipated induction of HMG CoA reductase (which increased approximately 4.4-fold). Conversely, phenobarbital produced large increases in liver microsomal enzymes, including glucuronosyl transferase, but did not affect the activity of HMG CoA reductase. Therefore, the increased clearance of thyroxine in simvastatin-treated female rats was not associated with enzyme induction but may have been related to the increase in functional liver mass produced by this compound at this dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Smith
P F
PF
Department of Safety Assessment, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
Grossman
S J
SJ
Gerson
R J
RJ
Gordon
L R
LR
Deluca
J G
JG
Majka
J A
JA
Wang
R W
RW
Germershausen
J I
JI
MacDonald
J S
JS
D000236:Adenoma / Q000139:chemically induced*; D000818:Animals; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006984:Hypertrophy; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008148:Lovastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D019821:Simvastatin; D013961:Thyroid Gland / Q000033:anatomy & histology / Q000187:drug effects / Q000473:pathology*; D013963:Thyroid Hormones / Q000097:blood; D013964:Thyroid Neoplasms / Q000139:chemically induced*; D013974:Thyroxine / Q000097:blood / Q000378:metabolism; D013997:Time Factors
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013963:Thyroid Hormones; D008148:Lovastatin; D019821:Simvastatin; D013974:Thyroxine; D010634:Phenobarbital