Alteration of thyroid homeostasis by UDP-glucuronosyltransferase inducers in rats: a dose-response study.
UDP-glucuronosyltransferase (UDP-GT) inducers have been shown to lower plasma levels of thyroxine (T4) by increasing its glucuronidation and elimination by the liver. However, there are no dose-response studies to address the relationship between induction of hepatic UDP-GT and alteration in thyroid homeostasis. Therefore, rats were fed a basal diet or a diet mixed with phenobarbital (PB: 600, 1200, 1800 or 2400 ppm), pregnenolone-16 alpha-carbonitrile (PCN: 250, 500, 1000 or 2000 ppm), 3-methylcholanthrene (3MC: 62.5, 125, 250 or 500 ppm) or a polychlorinated biphenyl mixture (Aroclor 1254, PCB: 10, 30, 100 or 300 ppm) for 15 days to determine their effects on hepatic UDP-GT induction, reduction of serum thyroid hormones and alteration of thyroid function. All the UDP-GT inducers produced a dose-dependent induction of hepatic UDP-GT activity toward T4; the increases produced by PCN (7-fold) and PCB (5-fold) were more pronounced than those produced by PB and 3MC (3-fold). Serum T4 (total and free T4) levels were reduced dramatically by the UDP-GT inducers in a dose-dependent manner (up to 50%-90%). However, they had no effect on serum free T3 and a minimal effect on decreasing serum total T3 levels (10%-20%). Reverse T3 levels were increased by all doses of PCN, by high doses of 3MC and by low doses of PCB. PCN produced a dose-dependent increase in serum thyroid-stimulating hormone (TSH) levels (up to 5-fold), and PB doubled TSH levels. Most surprisingly, even though 3MC and PCB decreased serum T4, they had minimal effects on TSH levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Liu
J
J
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, USA.
Liu
Y
Y
Barter
R A
RA
Klaassen
C D
CD
D000818:Animals; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D004435:Eating; D004790:Enzyme Induction; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D009929:Organ Size; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013961:Thyroid Gland / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D013963:Thyroid Hormones / Q000097:blood
D013963:Thyroid Hormones; D011285:Pregnenolone Carbonitrile; D008748:Methylcholanthrene; D011078:Polychlorinated Biphenyls; D014453:Glucuronosyltransferase; D010634:Phenobarbital