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 (T-4) by increasing its glucuronidation an d elimination by the liver. However, there are no dose-response studie s to address the relationship between induction of hepatic UDP-GT and alteration in thyroid homeostasis. Therefore, rats were fed a basal di et 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 polychlo rinated biphenyl mixture (Aroclor 1254, PCB: 10, 30, 100 or 300 ppm) f or 15 days to determine their effects on hepatic UDP-GT induction, red uction of serum thyroid hormones and alteration of thyroid function. A ll the UDP-GT inducers produced a dose-dependent induction of hepatic UDP-GT activity toward T-4; the increases produced by PCN (7-fold) and PCB (5-fold) were more pronounced than those produced by PB and 3MC ( 3-fold). Serum T-4 (total and free T-4) levels were reduced dramatical ly by the UDP-GT inducers in a dose-dependent manner (up to 50%-90%). However, they had no effect on serum free T-3 and a minimal effect on decreasing serum total T-3 levels (10%-20%). Reverse T-3 levels were i ncreased 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-stimulat ing hormone (TSH) levels (up to 5-fold), and PB doubled TSH levels. Mo st surprisingly, even though 3MC and PCB decreased serum T-4, they had minimal effects on TSH levels. Of the four UDP-GT inducers, PCN, PB a nd PCB increased I-131 uptake by the thyroid and caused thyroid hypert rophy, whereas thyroid weight and uptake of I-131 were affected minima lly by 3MC treatment. In conclusion, although all four UDP-GT inducers produced a dose-dependent induction of thyroxine glucuronidation and reduction of serum T-4 levels, their effects on TSH secretion and thyr oid functions are variable. It appears that elevated TSH is a better i ndicator of the effects of UDP-GT inducers on thyroid function than is increased UDP-GT or lowered T-4.