Comparison of the effects of propylthiouracil, amiodarone, diphenylhydantoin, phenobarbital, and 3-methylcholanthrene on hepatic and renal T4 metabolism and thyroid gland function in rats.
We studied the effects of propylthiouracil (PTU), amiodarone (AMIO), diphenylhydantoin (DPH), phenobarbital (PB), and 3-methylcholanthrene (MC) on thyroid histomorphology, on the hepatic and renal enzymes involved in endogenous and exogenous metabolism, and on the plasma levels and pharmacokinetics of thyroid hormones after 7 and 14 days of treatment. PTU and PB, by decreasing both serum tetraiodothyronine (T4) and triiodothyronine (T3), induced a massive increase in serum thyrotropin (TSH) and thus induced thyroid hypertrophy. AMIO and MC, by decreasing respectively serum T3 and T4, also induced an increase of TSH, but to a lesser extent, not sufficient to induce thyroid hypertrophy. Hepatic 5'-deiodinase activity was decreased in all treated rats. Inhibition of this enzyme by PTU was demonstrated in vitro; AMIO also decreased the enzyme activity by a still unelucidated mechanism, which probably requires intact cell plasma membranes, whereas in PB- and MC-treated rats the decrease in enzyme activity certainly resulted from decreased serum concentrations of T4. In PTU-treated rats, and probably in MC-treated rats, decreases in circulating thyroid hormones were primarily due to impairment of synthesis and/or of secretion by the thyroid. In contrast, in PB-treated rats, the decrease in serum thyroid hormone levels seems to be due to increased excretion of these hormones, as T4 serum clearance was significantly increased. PB, a microsomal enzyme inducer, increased the cytochrome b5 and P450 content as well as the cytochrome P450-dependent O-depentylation of pentoxyresorufin. The other type of enzyme inducer, MC, did not affect cytochrome b5 and P450 levels, but did increase the cytochrome P450 dependent O-deethylation of ethoxyresorufin. PB increased the glucuronidation of morphine, whereas MC increased the glucuronidation of 1-naphthol. However, serum T4 clearance, mainly determined by its hepatic conjugation rate, was increased only in PB-treated rats. It appears from this study that the close metabolic relationship between the liver/kidney and the thyroid should be taken into consideration when the findings of chronic toxicology and carcinogenicity studies are interpreted.
De Sandro
V
V
Rhône-Poulenc Rorer, Département Sécurité du Médicament, Centre de Recherche de Vitry-Alfortville, Vitry sur Seine, France.
Chevrier
M
M
Boddaert
A
A
Melcion
C
C
Cordier
A
A
Richert
L
L
D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015786:Cytochromes b5 / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010105:Oxygenases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D010672:Phenytoin / Q000494:pharmacology*; D011441:Propylthiouracil / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013961:Thyroid Gland / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood / Q000378:metabolism*; D014284:Triiodothyronine / Q000097:blood
D014284:Triiodothyronine; D008748:Methylcholanthrene; D010672:Phenytoin; D011441:Propylthiouracil; D013972:Thyrotropin; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D014453:Glucuronosyltransferase; D000638:Amiodarone; D013974:Thyroxine; D010634:Phenobarbital