Heavy metals and lysosomes.

Much can be gained by reassessing the processes which determine the ability of lysosomes to take up or exclude, sequester and mobilize heavy metals. To achieve a better understanding of these events, the chemical forms, intracellular pathways and modes of delivery of metals to lysosomes, as well as the specific physiologic ligands and molecular targets susceptible to metal toxicity have to be identified. None of these can be derived from measurements of metal contents of whole lysosomal fractions because the metal's "effective concentration" at a specific target site may be affected by the binding properties of the lysosomal ligand as well as by those of cation carrier proteins present in the cytosol (e.g., metallothionein), and by interactions with and competitions by other cellular organelles. Therefore, the possibility of such events diminishing or enhancing a metal's direct effect observable in in vitro systems has to be considered before extrapolating to the in vivo situation. Another pitfall to be wary of is the equation of an organelle's relative affinity for a metal in vitro with its susceptibility to the metal's toxic effects. This is evident, albeit at a tissue level rather than at that of organelles, from the discordance between the low affinity of nervous tissue for lead and this metal's pronounced encephalopathic effect. The answers to some of the questions raised in this review may possibly lead to pharmacologic applications, particularly to the development of effective agents for the removal from or the inactivation of toxic metals deposited in lysosomes. At present, considerable uncertainty exists regarding the possible interaction of therapeutic chelating agents with lysosomes in vivo. We do not know, for example, whether the contrasts between the remarkable effectiveness of penicillamine in mobilizing copper from tissues and the limited effectiveness of desferioxamine in removing excess iron stores can be accounted for by differences in accessibility of these two chelators to lysosomes. Or, alternatively, can these differences in effectiveness be related to different ligands or macromolecules interacting with each metal? At least part of the lysosomal iron is bound to ferritin molecules which may not be susceptible to the action of chelating agents after incorporation. Such speculation is not without foundation since ferritin molecules are heterogeneous. However, whether this heterogeneity, which is reflected in different organ-specific patterns of distribution (Powell et al. 1973), is the result of differing affinities of the isoferritins for specific subcellular organelles has not been established. It is conceivable that ferritin molecules present in the cytoplasm may be subtly different from those taken up by lysosomes, implying that the latter are endowed with capabilities for selection of specific macromolecules...