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  • DNA alkylation  (2)
  • 1
    ISSN: 1432-1335
    Keywords: Liver cells ; Cell cycle ; DNA alkylation ; O6-Methylguanine repair
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To compare the formation and persistance of alkylated DNA bases in the G1- and S-phase compartments in liver in vivo, regnerating rat liver was exposed to [14C]dimethylnitrosamine (0.57 mg/kg, IP injection) or N-[methyl 14C]-N-nitrosourea (3.3 mg/kg, intraportal injection) during the G1 phase of the cell cyle (12 h after partial hepatectomy), or at 24 h after partial hepatectomy with 30% hepatocytes in DNA synthesis, or at 43 h after partial hepatectomy, 4 h after an hydroxyurea block from 14 to 39 h after operation with 80% hepatocytes in DNA synthesis. At 120 min after dimethylnitrosamine and 90 s, 5, 10, or 60 min after the intraportal pulse of N-methyl-N-nitrosourea the molar fractions of 7-methylguanine (7megua), O6-methylguanine (O6megua), and 3-methyladenine (3mead) and of metabolically labeled guanine were determined from DNA hydrolysates by Sephadex-G10 radiochromatography. After dimethylnitrosamine only minor differences were observed for 7megua formation in the three groups; the 3mead/7megua ratio remained constant irrespective of the number of cells in S phase. In contrast, the O6megua/7megua ratio revealed a loss of O6megua, the extent of which appeared proportional to the fraction of DNA-synthesizing cells in the liver. The rapid loss of O6megua in S-phase cells was confirmed after intraportal administration of N-methyl-N-nitrosourea. During the first 10 min after the methylnitrosourea pulse the O6megua/7megua ratio was constant in G1 cells and dropped from 90 s to 10 min by about 15% in liver containing 30% S-phase cells and by about 40% with 80% cells in DNA synthesis. DNA-synthesizing hepatocytes are apparently endowed with a higher O6megua DNA transferase activity than nonproliferating liver cells. The rapid, though exhaustible elimination of O6megua during S-phase might result in partial protection of DNA-synthesizing cells from base-mispairing and/or from hypomethylation at G-C sites.
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  • 2
    ISSN: 1432-1335
    Keywords: Regenerating liver ; Cell cycle ; O6-Methylguanine DNA transferase ; DNA alkylation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary O6-Methylguanine DNA transferase activity was investigated in liver proteins obtained at various intervals after partial hepatectomy and/or after hydroxyurea-induced synchronization of the liver cell cycle. Liver proteins were incubated with 3H-methylated calf thymus DNA as previously described by Pegg et al. (1981). The loss of O6-methylguanine was measured by radiochromatography of DNA hydrolysates. The extent of O6-methylguanine repair differed during the cell cycle: the activity increased in late G1, reached a maximum in early S phase and declined in late S phase and G2M. These results indicate that hepatocytes are endowed with an increased DNA repair capacity for this promutagenic lesion during the period of highest transformation sensitivity in the cell cycle. Though increased, however, this repair potential does not, because of its exhaustibility, appear to be sufficient to prevent initiation of transformation after high doses of alkylating carcinogens.
    Type of Medium: Electronic Resource
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