Abstract
The traditional Chinese medicine Schisandra chinensis has remarkable protective effects against chemical-induced toxicity. Cyclophosphamide (CTX), in spite advances in chemotherapy and immunosuppressive regimes, is prone to cause severe toxicity due to its chloroacetaldehyde (CAA) metabolite produced by CYP3A. Our previous study identified that S. chinensis extract (SCE) co-administration potently decreased CAA production and attenuated liver, kidney and brain injuries in CTX-treated rats. Gomisin A (Gom A) is proved to be one of the most abundant bioactive lignans in S. chinensis with a significant CYP3A inhibitory effect. To find out whether and how Gom A participated in the chemoprevention of SCE against CTX toxicity, the Gom A-caused CYP3A inhibition in vitro as well as the pharmacokinetic interactions between Gom A and CTX in vivo were examined in this study. Using human liver microsomes, a reversible inhibition assay revealed that Gom A was a competitive inhibitor with a KI value of 1.10 µM, and the time- and NADPH-dependent CYP3A inhibition of Gom A was observed in a time-dependent inhibition assay (KI = 0.35 µM, kinact = 1.96 min−1). Hepatic CYP3A mRNA expression experienced a significant increase in our rat model with Gom A administration. This explained why CAA production decreased in the 0.5 h- and 6 h-pretreatment rat groups while it increased in the 24 h- and 72 h-pretreatment groups, indicating a bidirectional effect of Gom A on CYP3A-mediated CTX metabolism. The present study suggested that Gom A participates like SCE in the pharmacokinetic intervention of CTX by blocking CYP3A-mediated metabolism and reducing CAA production, and thus plays an important role in the chemopreventive activity of S. chinensis against CTX toxicity, in addition to the previously recognized protective effects. Also, the combined use of S. chinensis preparation or other drugs containing Gom A as the main component with CTX needed to be addressed for better clinical intervention.
Highlights
Chemotherapy has been an integral part of cancer treatment for decades, the numerous side effects are a major concern limiting its usage and causing patients’ unwanted clinical consequences in the long-term
By an NADPH-dependence assay, the CYP3A-inhibition was found more potent when Gomisin A (Gom A) was additional NADPH-dependence assay, the CYP3A-inhibition was found more potent when preincubated with NADPH
The time interval between S. chinensis and CTX administration was 0.5 h, which meant than Gom A exhibited a strong inhibitory effect on rat hepatic CYP3A activity when
Summary
Chemotherapy has been an integral part of cancer treatment for decades, the numerous side effects are a major concern limiting its usage and causing patients’ unwanted clinical consequences in the long-term. Schisandra chinensis and reliable resource for investigations, cancer chemoprevention [1]. A aa significant change in some biochemical indexes such as serum marker enzymes.significant change in pharmacokinetic parameters was along the toxicity [8]. CYP2B6 and metabolized into the effective component immunosuppressive therapy [10]. It is mainly activated by CYP2B6 and metabolized into the phosphoramide phosphoramide mustard [11].
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