Nuclear binding as a determinant of tissue distribution of adriamycin, daunomycin, adriamycinol, daunorubicinol and actinomycin D.
The tissue distribution mechanism of adriamycin (ADR), its relatives, daunomycin (DNR), adriamycinol (ADR-ol), daunorubicinol (DNR-ol) and actinomycin D (ACT-D) has been studied in rats and rabbits. The following evidences with respect to tissue distribution of ADR were obtained: 1) remarkable binding of ADR to tissue homogenate, 2) significant difference in the tissue binding of ADR among tissues, 3) exclusive localization of ADR in cell nucleus, 4) good correlation between the tissue binding of ADR and the tissue desoxyribonucleic acid (DNA) concentration, 5) comparatively good coincidence between the experimentally determined tissue binding of ADR and that calculated from in vitro nuclear binding parameters reported and the tissue DNA concentration, and 6) no correlation between the concentration of tissue phospholipids (i.e. cardiolipin, acidic phospholipids and total phospholipids) and the Kp value of ADR in rats. From these findings, it was confirmed that the nuclear binding is a determinant of the extensive tissue distribution of ADR and that a remarkable variation in the tissue concentration of ADR is due mainly to the difference in the tissue DNA concentration. Furthermore, good correlations were demonstrated between the DNA concentration and Kpapp values of DNR and ACT-D in rats and DNR, ADR-ol and DNR-ol in rabbits. Hence, it is suggested that there is a common mechanism of in vivo tissue distribution of ADR and its relatives which can intercalate to DNA and the determinant of characteristic tissue distribution is nuclear binding of these antibiotics.
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D004247:DNA / Q000032:analysis; D003609:Dactinomycin / Q000378:metabolism*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000378:metabolism*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism*; D066298:In Vitro Techniques; D011817:Rabbits; D051381:Rats; D014018:Tissue Distribution
D003609:Dactinomycin; D004317:Doxorubicin; D004247:DNA; C010013:adriamycinol; C000847:daunorubicinol; D003630:Daunorubicin