Time- and NADPH-Dependent Inhibition on CYP3A by Gomisin A and the Pharmacokinetic Interactions between Gomisin A and Cyclophosphamide in Rats

Jianxiu Zhai; Feng Zhang; Shouhong Gao; Li Chen; Ge Feng; Jun Yin; Wansheng Chen

doi:10.3390/molecules22081298

Molecules (Aug 2017)

Time- and NADPH-Dependent Inhibition on CYP3A by Gomisin A and the Pharmacokinetic Interactions between Gomisin A and Cyclophosphamide in Rats

Jianxiu Zhai,
Feng Zhang,
Shouhong Gao,
Li Chen,
Ge Feng,
Jun Yin,
Wansheng Chen

Affiliations

Jianxiu Zhai: School of Traditional Chinese Materia, Shenyang Pharmaceutical University, Shenyang 110016, China
Feng Zhang: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China
Shouhong Gao: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China
Li Chen: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China
Ge Feng: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China
Jun Yin: School of Traditional Chinese Materia, Shenyang Pharmaceutical University, Shenyang 110016, China
Wansheng Chen: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China

DOI: https://doi.org/10.3390/molecules22081298
Journal volume & issue: Vol. 22, no. 8
p. 1298

Abstract

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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.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

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