Abstract
Diurnal susceptibility to medical drugs have often been demonstrated and known as chronotherapy. However, such observations especially about heavy metals are still scarce. We report the diurnal susceptibility to cadmium toxicity in mice. Male C57BL/6J mice kept in cages on 8:00-20:00 L/D cycle were administrated intraperitoneally (i.p.) with cadmium chloride at 6 different clock time (10:00, 14:00, 18:00, 22:00, 2:00 and 6:00 h), describing as zeitgeber time (ZT); ZT2, ZT6, ZT10, ZT14, ZT18 and ZT22. In case of dark period (ZT14, ZT18 and ZT22), administrations were performed under red light. Mortalities were monitored until 14 days after the injection. Surprisingly, all mice were dead at ZT2 injection; conversely, all mice were survived at ZT18 injection. The hepatotoxicity was estimated 24 hr after the Cd injection using the plasma GPT values as an index. The GPT value was markedly elevated at ZT6 injection while not any changed at ZT18 injection. In ZT6 and ZT18, there were no difference in hepatic Cd accumulation, metallothionein (MT) induction level, further, both basal hepatic MT level and GSH level. When hepatic GSH level was depressed by L-buthionine-[S,R]-sulfoximine, however, the difference in hepatotoxic susceptibility was clearly disappeared. We showed the clear diurnal variation of Cd-induced toxicity and one of the candidate factors for determination of this variation was GSH.
