Resistance to Hepatotoxins Acquired by Hepatocytes during Liver Regeneration1

The appearance of resistance to a number of hepatotoxins ¡nprimary cultures of hepatocytes prepared at various time intervals up to 2 weeks after partial hepatectomy is the major focus in this study. Resistance to the cytocidal effect of aflatoxin Bi, 2-acetylaminofluorene, N-hydroxy-2-acetylaminofluorene, methotrexate, or methyl methanesulfonate shows a pro gressive increase until 48 hr and then returns to the resting level of susceptibility by 2 weeks. The genesis of mutagens from 2-acetylaminofluorene and aflatoxin B, by S-9 liver frac tions shows a decrease from and return to control values after partial hepatectomy that parallels the resistance. The levels of total cellular cytochromes P-450 also decrease following partial hepatectomy and remain from 28 to 36% less than those of controls for at least 1 week. The glutathione and total soluble sulfhydryl ("glutathione") content increase following partial hepatectomy, and the pattern is consistent with a partial role for glutathione in the resistance phenomenon as it relates to 2acetylaminofluorene. The possible relationship between resist ance to the cytocidal effects in vitro and the resistance to inhibition of cell proliferation in vivo during liver carcinogenesis is discussed.