Abstract
AIMS: Heart failure is a life-threatening complication of high-dose cyclophosphamide (CTX) chemotherapy, and the present study aimed at identifying the mechanism involved in mice. METHODS AND RESULTS: CTX at 800 mg/kg resulted in heart failure, in which cytoplasmic thioredoxin reductase (TrxR1) activity and non-protein free thiol (NPFT) level were suppressed by 90 and 62%, respectively. The combination of 350 mg/kg CTX and the glutathione synthesis inhibitor buthionine sulfoximine (BSO) also evoked heart failure, in which TrxR1 activity and NPFT level were suppressed by 66 and 62%, respectively. NPFT depletion alone by BSO did not cause cardiac toxicity. CTX at 350 mg/kg alone also did not cause cardiac toxicity, even though it suppressed TrxR1 activity by 68%. Previous studies have shown that half inactivation of TrxR1 in tumour, bladder, and kidneys was associated with toxicological consequences. Cardiac TrxR1 is dispensable, but cardiac cytoplasmic thioredoxin (Trx1) is essential. The potential uncoupling between TrxR1 and Trx1 may explain why there is no cardiac toxicity following TrxR1 inhibition. However, TrxR1 inactivation may still play a role in CTX-evoked heart failure because inactivated TrxR1 gains cytotoxic function, which may engender noticeable toxicity when massive NPFT is deleted. CONCLUSION: CTX-evoked heart failure involves pronounced co-suppression of TrxR1 activity and NPFT level.