Non-carcinogenicity, but dose-related increase in preneoplastic hepatocellular lesions, in a two-year feeding study of phenobarbital sodium in male F344 rats.
Phenobarbital sodium (PB) was administered at dietary levels of 0 (control), 8, 30, 125 and 500 ppm to groups of 20 male F344/DuCrj rats for 104 weeks. There were no treatment-related clinical signs or adverse effects on survival rate, body weights, food consumption, and haematology or blood biochemistry data. Statistically significant increases of relative liver weights were found in the 500 and 125 ppm, but not the 30 and 8 ppm groups. Quantitative analysis of glutathione S-transferase placental form positive (GST-P+) hepatocyte foci/areas revealed clear increases limited to the 500 and 125 ppm groups. Western blotting revealed CYP2B1, 2C6 and 3A2 proteins to be also increased only with these high doses. In addition, significant increase of regenerative hepatocellular hyperplasias was noted in the 500 ppm group. No hepatocellular adenomas were observed, but a hepatocellular carcinoma arose in single rats of the 8 ppm and 125 ppm groups. No treatment-related changes were found in any other organs or tissues. Thus, under the experimental conditions used, the highest dose of PB (500 ppm) was not carcinogenic in male F344 rats. Furthermore, increase in putative preneoplastic proliferative hepatocytic lesions was only noted with 500 and 125 ppm.
Hagiwara
A
A
Daiyu-kai Institute of Medical Science, Nishiazai, Ichinomiya, Japan.
Miyata
E
E
Tamano
S
S
Sano
M
M
Masuda
C
C
Funae
Y
Y
Ito
N
N
Fukushima
S
S
Shirai
T
T
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004435:Eating; D004798:Enzymes / Q000097:blood; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000032:analysis; D006403:Hematologic Tests; D006965:Hyperplasia; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000008:administration & dosage / Q000633:toxicity*; D011230:Precancerous Conditions / Q000097:blood / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate; D013963:Thyroid Hormones / Q000097:blood; D013997:Time Factors
D002273:Carcinogens; D004798:Enzymes; D007527:Isoenzymes; D013963:Thyroid Hormones; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496558:Gstp1 protein, rat; D010634:Phenobarbital