Acetaminophen alters estrogenic responses in vitro: inhibition of estrogen-dependent vitellogenin production in trout liver cells

The purpose of this study was to determine if acetaminophen altered estroge n-dependent vitellogenin production in isolated trout liver cells. Estrogen -induced vitellogenesis was studied in liver cells isolated from male trout and cultured in defined medium; vitellogenin secreted into culture medium was quantitated using immunological procedures. Vitellogenin production was absolutely dependent on the addition of estradiol (10(-6) M) to liver cell s from male trout. Acetaminophen produced a dose-dependent inhibition of vi tellogenin production; similar to 50% inhibition was achieved with 0.05 mM acetaminophen, while 0.3 mM acetaminophen inhibited secreted vitellogenin t o undetectable levels. In contrast, these concentrations of acetaminophen ( less than or equal to 1 mM) did not significantly alter the production of s ecreted albumin, determined immunologically, or cause detectable toxicity. Higher doses of acetaminophen were toxic, but did not induce DNA fragmentat ion in the trout liver cells. Acetaminophen reduction of estradiol-induced vitellogenin production was accompanied by a dose-dependent decrease in vit ellogenin mRNA, indicating acetaminophen inhibited a step prior to, or duri ng, formation of vitellogenin mRNA. Estrogen receptor-binding assays demons trated that acetaminophen did not reduce binding of [H-3]-estradiol to trou t liver estrogen receptor. In addition, catabolism of estradiol to water-so luble metabolites was not significantly altered by acetaminophen. These stu dies indicate that non-toxic concentrations of acetaminophen specifically i nhibit estrogen-dependent vitellogenin synthesis and suggest that this comm only used drug may alter estrogen-regulated processes.