Enhanced levels of several mitochondrial mRNA transcripts and mitochondrial superoxide production during ethinyl estradiol-induced hepatocarcinogenesis and after estrogen treatment of HepG2 cells.
Ethinyl estradiol (EE) is a strong hepatic promoter and weak complete hepatocarcinogen. Among the effects on rat liver caused by chronic exposure to non-hepatotoxic doses of EE is an initial, transient increase in hepatocyte growth followed by a subsequent inhibition (mitosuppression) of basal and/or induced liver growth. To investigate the mechanism of EE-induced mitosuppression, we performed a differential display and identified 10 genes whose expression was increased 2- to 4-fold in EE-induced, mitosuppressed livers (Chen et al., Carcinogenesis, 17, 2783-2786, 1996). We found that one of these clones was homologous to nuclear genome-encoded mitochondrial ATP synthase subunit E. Here, we describe the identification of two additional cDNAs representing transcripts whose levels were elevated during EE-induced mitosuppression as mitochondrial DNA-encoded cytochrome c oxidase subunit III and ATP synthase 6. In addition, we found that EE, estradiol and the estradiol catechol metabolites, 4-OH-estradiol and 2-OH-estradiol, increased the levels of these and other mitochondrial genome-encoded transcripts in human hepatoma HepG2 cells. We also observed that this increase can be blocked by inhibition of cytochrome P450-mediated estrogen metabolism, and that this increase is accompanied by increased mitochondrial superoxide production, which reflects increased respiratory chain activity.
Chen
J
J
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205-2179, USA.
Gokhale
M
M
Li
Y
Y
Trush
M A
MA
Yager
J D
JD
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002396:Catechols / Q000378:metabolism / Q000633:toxicity; D018076:DNA, Complementary / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000633:toxicity; D004997:Ethinyl Estradiol / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013481:Superoxides / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D002396:Catechols; D018076:DNA, Complementary; D004272:DNA, Mitochondrial; D012333:RNA, Messenger; D013481:Superoxides; D004997:Ethinyl Estradiol; D004958:Estradiol; D006180:Proton-Translocating ATPases