Promotion of thyroid carcinogenesis by para-aminobenzoic acid in rats initiated with N-bis(2-hydroxypropyl)nitrosamine.
Sulfonamide analogues of para-aminobenzoic acid (PABA), a precursor of folate synthesis, have beneficial effects as antifolate, but thyroid peroxidase inhibition has been reported as a side effect that results in promotion of rat thyroid carcinogenesis. In the present study, effects of PABA itself on F344 rat thyroid carcinogenesis after initiation with N-bis(2-hydroxypropyl)nitrosamine (DHPN) were evaluated. In experiment 1, rats in groups 1-4 received a single subcutaneous injection of DHPN at 2800 mg/kg, and groups 5 and 6 received vehicle saline alone. From 1 week after DHPN initiation, rats in groups 2, 3, 4, and 6 were fed basal diet containing 0.25%, 0.5%, 1.0%, and 1.0% PABA, respectively, for 40 weeks. Rats in groups 1 and 5 received basal diet alone throughout the experiment. The final incidence of thyroid follicular cell adenomas and adenocarcinomas was significantly (p < 0.05 or 0.01) increased in groups 3 and 4 as compared to group 1. No thyroid tumors were found in groups 5 and 6. In experiment 2, animals in group 1 were fed basal diet alone, while groups 2 and 3 were given 0.5% and 1.0% PABA in the diet, respectively, for 2 weeks. Thyroid weights in group 3, and serum thyroid stimulating hormone level and proliferative activity of follicular cells in groups 2 and 3 were significantly (p < 0.05 or 0.01) elevated. In addition, the serum thyroxine level in group 3 was significantly (p < 0.05) depressed. These results clearly indicate that PABA exerts promotion/progression effects on rat thyroid carcinogenesis as a result of hypothyroidism followed by negative-feedback via the thyroid-pituitary axis.
Hasumura
M
M
Division of Pathology, National Institute of Health Sciences, Kamiyoga, Tokyo 158-8501, Japan.
Imai
T
T
Takizawa
T
T
Ueda
M
M
Onose
J
J
Hirose
M
M
D010129:4-Aminobenzoic Acid / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D005247:Feeding Behavior / Q000187:drug effects; D008297:Male; D009602:Nitrosamines / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013963:Thyroid Hormones / Q000097:blood; D013964:Thyroid Neoplasms / Q000097:blood / Q000139:chemically induced* / Q000473:pathology
D002273:Carcinogens; D009602:Nitrosamines; D013963:Thyroid Hormones; C012457:diisopropanolnitrosamine; D010129:4-Aminobenzoic Acid