Changes in the ornithine cycle following ionising radiation cause a cytotoxic conditioning of the culture medium of H35 hepatoma cells.
Cultured H35 hepatoma cells release a cytotoxic factor in response to irradiation with X-rays. When the conditioned medium from irradiated cells is given to nonirradiated cells, growth is inhibited and followed by cell death, possibly apoptosis, Analysis of the conditioned medium reveals a dramatic change in the ornithine (urea) cycle components after the irradiation. A strong decrease in medium arginine is accompanied with parallel increases in ornithine, citrulline and ammonia. The high level of ammonia appears to be largely responsible for the observed cytotoxicity. The development of hyperammonia by irradiated cells and the related toxicity depend on the radiation dose and the number of cells seeded thereafter for the medium conditioning. Development of cytotoxicity by irradiated cells is completely prevented with the arginase inhibitor L-norvaline, in arginine-deficient medium or when citrulline replaces arginine. These preventive measures result in subtoxic ammonia levels.
van Rijn
J
J
Radiation Oncology, VU Medical Center, Amsterdam, The Netherlands. j.vanrijn@vumc.nl
van den Berg
J
J
Teerlink
T
T
Kruyt
F A E
FA
Schor
D S M
DS
Renardel de Lavalette
A C
AC
van den Berg
T K
TK
Jakobs
C
C
Slotman
B J
BJ
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D009952:Ornithine / Q000378:metabolism*; D011829:Radiation Dosage; D051381:Rats; D013223:Statistics as Topic; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D009952:Ornithine