Studies Of The Excretion Of Aluminium By The Kidney And The Toxic Effects Of The Element On Dna

ABSTRACT

THESIS TITLE: Studies of the excretion of aluminium by

the kidney and the toxic effects of the element on DNA.

CANDIDATE: Felix Salvador Emilio Monteagudo, c/o

Department of Pharmacology, University of Cape Town, Cape

Town. February, 1991.

Aluminium is an element of increasing clinical

importance. It not only has uses as a medicinal substance

but also in recent years it has been shown to be the

cause of considerable toxicity, particularly in the

setting of chronic renal failure. Diseases that have

been shown to be associated with aluminium, or in which

it has been implicated, include dialysis dementia, renal

osteodystrophy and Alzheimer's disease.

This thesis has studied aspects of the interaction

between aluminium and the kidney. The work has addressed

two major issues.

Firstly, a study is

technique was used to

tubular site for Al in

excreted in the distal

described where Malvin's stop-flow

determine any excretory/absorptive

the pig kidney. Al was found to be

nephron of the pig kidney.

Secondly, the toxic effects of

pig kidney cell line LLC-PKl

attempt to elucidate some of

action.

Al in vitro on the DNA of

were investigated, in an

the mechanisms of toxic

DNA synthesis was measured using 3 H-TdR incorporation.

Over increases of both time (9-72 h) and Al concentration

(0.01-8.0 mM), 3 H-TdR incorporation was diminished.

Effects were evident at concentrations as low as 0.05 mM

Al.

The production of DNA strand breaks was assessed by the

increase in size of cell nucleoids (ie DNA in supercoiled

form). Nucleoid size was analyzed in a Epics 753

Fluorescence Activated Cell Sorter interfaced with an

MDADSII data acquisition and analysis system. After 90

min incubation with Al (over the concentration range

0.001-32 mM), an increase in nucleoid size was noted at

concentrations above 0.05 mM.

The data demonstrate that Al exerts an effect on kidney

cells in vitro which is expressed as diminished DNA

synthesis and production of DNA strand breaks. These

effects on DNA may have important long-term implications

on various disease states associated with Al toxicity.