Comparative distribution, metabolism, and utilization of phylloquinone and menaquinone-9 in rat liver.

The liver of most species contains a spectrum of bacterially produced menaquinone homologs as well as the major dietary form of vitamin K, phylloquinone. The relative utilization of phylloquinone and menaquinone-9 (MK-9) as substrates for the microsomal vitamin K-dependent gamma-glutamyl carboxylase was determined in a rat model. Vitamin K 2,3-epoxide, the co-product of the carboxylation reaction, is recycled to the quinone form of the vitamin by a microsomal vitamin K epoxide reductase. This enzyme activity was blocked by warfarin administration, and the appearance of the hepatic epoxides of phylloquinone and MK-9 was determined as a measure of their utilization by the carboxylase. When the liver contained equimolar amounts of phylloquinone and MK-9, four times as much phylloquinone epoxide as MK-9 epoxide was present in the liver 1 hr after warfarin administration. These data suggest that hepatic MK-9 is not as efficiently utilized as phylloquinone. The data obtained have also demonstrated a previously unrecognized difference in phylloquinone and menaquinone metabolism. MK-9 epoxide, and to a lesser extent MK-9, was preferentially localized in the mitochondria, while higher concentrations of phylloquinone were found in the microsomes.

Nonrandom cytogenetic changes accompany malignant progression in clonal lines abelson virus-infected lymphocytes.

Initially, lymphoid cells transformed by v-abl or BCR/ABL oncogenes are poorly oncogenic but progress to full transformation over time. Although expression of the oncogene is necessary to initiate and maintain transformation, other molecular mechanisms are thought to be required for full transformation. To determine whether tumor progression in ABL oncogene-transformed lymphoid cells has a genetic basis, we examined whether progression of the malignant phenotype of transformed clones correlates with particular cytogenetic abnormalities. A modified in vitro bone marrow transformation model was used to obtain clonal Abelson murine leukemia virus-transformed B lymphoid cells that were poorly oncogenic. Multiple subclones were then derived from each clone and maintained over a marrow-derived stromal cell line for several weeks. Over time, clonally related Abelson murine leukemia virus-transformed subclones progressed asynchronously to full transformation. The data show that tumor progression can occur in the absence of detectable cytogenetic changes but, more importantly, that certain cytogenetic abnormalities appear reproducibly in highly malignant subclones. Therefore, three independent subclones showed deletion in a common region of chromosome 13. Other highly malignant cells carried a common breakpoint in the X chromosome, and, finally, two subclones carried an additional chromosome 5. These results are consistent with the hypothesis that ABL oncogenes are sufficient for the initial transformation of cells but that additional genetic events can drive oncogenic progression. These observations further suggest that diverse genetic mechanisms may be able to drive tumor progression in cells transformed with ABL oncogenes.