Heme regulation in mouse mammary carcinoma and liver of tumor bearing mice—I. Effect of allyl-isopropylacetamide and veronal on δ -aminolevulinate synthetase, cytochrome P-450 and cytochrome oxidase

Nora M Navone,Cesar F Polo,Rodolfo M Dinger,Alcira M Del C Batlle

doi:10.1016/0020-711x(90)90207-j

Abstract

1. 1. Basal levels and allyl-isopropylacetamide (AIA) or veronal induced levels of δ-aminolevulinate synthetase (ALA-S), cytochrome P-450 (cyt P-450) and cytochrome oxidase were determined in tumor (T) and liver of both normal mice (NM) and T bearing mice (TBM). 2. 2. Basal levels of ALA-S were nearly the same in either source. The amount of cyt P-450 was lower in TBM liver than in NM liver, and no detectable in T. While the basal activity of cytochrome oxidase in TBM liver and T were higher than those of NM liver. 3. 3. In AIA intoxicated animals there was a lower induction of ALA-S in liver of TBM than in NM liver. There was no induction in T ALA-S. The loss of cyt P-450 was less in TBM liver when compared with NM liver. 4. 4. The induction level of cyt P-450 after veronal administration was nearly the same in liver of both TBM and NM. 5. 5. We conclude that lower induction of liver ALA-S activity in TBM liver is due to correspondingly lower drug metabolism ability of TBM liver. Otherwise our results suggest that the control mechanism operating in T and probably in its original tissue are different from those described for normal liver.

Highlights

We could provide some more evidence as to explain the reasons why the levels of ALA-S activity in liver of T bearing mice (TBM) treated with AIA are lower than in normal mice (NM)
If we take into account that the basal levels of cyt P-450 were lower in TBM liver than in NM liver, that the amount of cyt P-450 was nearly equal in liver of both TBM and NM after AIA administration, in other words that the loss of cyt P-450 was less in TBM liver and that AIA exerts its porphyrinogenic action only after having been metabolized by cyt P-450, it is clear that lower induction of liver ALA-S activity in TBM liver is due to the corresponding lower drug metabolizing ability of TBM liver
We have found that Verona1 did not induce ALA-S, but slightly reduced in either liver from TBM or NM and it did increase cyt P-450 content up to nearly the same levels in both TBM and NM liver

Summary

INTRODUCTION

Is the rate limiting and regulatory enzyme in heme pathway. Administration of porphyrinogenic drugs to animals greatly increased liver ALA-S activity (Granick, 1966). A consistent feature of the chemically induced preneoplastic hepatocyte is their relative resistance to hepatotoxins (Eriksson et al, 1983; Farber et al, 1976). This fact is concordant with metabolic alterations that diminished the capacity of transformed cells to activate xenobiotics to species of high reactiveness (Stout and Becker, 1978). Stout and Becker (1986) found an increased capacity of heme degradation and a decreased heme synthesis as well as a diminished amount of a number of nonmitochondrial heme proteins in cells arising from chemically induced mouse liver tumors (T). With the aim of obtaining information as to the regulation mechanism operating in T, liver of T bearing mice (TBM) and liver of normal mice (NM), basal levels and AIA or veronal induced levels of ALA-S, cyt P-450 and cytochrome oxidase were determined

MATERIALS AND METHODS

RESULTS

DISCUSSION