Involvement of organic cation transporter 1 and CYP3A4 in retrorsine-induced toxicity

Tu, Meijuan; Li, Liping; Lei, Hongmei; Ma, Zhiyuan; Chen, Zhongjian; Sun, Siyuan; Xu, Siyun; Zhou, Hui; Zeng, Shaohua; Jiang, Huidi

doi:10.1016/j.tox.2014.04.007

Cited by 38 publications

(45 citation statements)

References 42 publications

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“…Lankas and his colleagues (Lankas et al 1998), but Tu et al reported that RTS is a weak substrate for P-glycoprotein (Tu et al 2014). We guess that may be the reason why RTS entered rat fetus through placenta barrier almost without obstacle.…”

Section: Discussionmentioning

confidence: 78%

Maternal-Fetal Disposition and Metabolism of Retrorsine in Pregnant Rats

Yang

Xiang

et al. 2018

Drug Metab Dispos

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The number of text pages: 21The number of figures: 7 The number of references: 44 The number of words in the Abstract: 276 The number of words in the Introduction: 625 The number of words in the Discussion: 1231 Abbreviations pyrrolizidine alkaloids, PAs; cytochrome P450, CYP; retrorsine, RTS; gestation day, GD; glutathione, GSH; glyceraldehyde phosphate dehydrogenase, GAPDH; 4-dimethylaminobenzaldehyde, DABA; hematoxylin and eosin, HE; declustering potential, DP; collision energy, CE; collision cell exit potential, CXP; highperformance liquid chromatography, HPLC; multiple-reaction monitoring, MRM; ATP-binding cassette, ABC AbstractPyrrolizidine alkaloids (PAs) are extensively synthesized by plants and are commonly present in herbs and foodstuffs, which exhibit hepatotoxicity requiring metabolic activation by cytochrome P450 (CYP) 3A to form the electrophilic metabolites-pyrrolic esters. PAs also cause embryo toxicity, but the metabolic profiles of PAs in fetus and placenta have been far from clear. In this study, we determined the basal metabolic activation of retrorsine (RTS) in rat maternal liver, placenta and fetal liver in vitro, and examined the fetal toxicity and bioactivation of RTS in vivo. Detection of microsomal RTS metabolites in vitro showed that the basal metabolic activity of fetal liver and placenta to RTS was much weaker than that of maternal liver. In addition, higher rate of pyrrolic ester formation was found in normal male fetal liver, compared with that of female pups. In vivo exposure to RTS caused fetal growth retardation as well as placenta and fetal liver injury. Little difference in serum RTS was observed in dams and fetuses, but the content of pyrrole-protein adduction in fetal liver was much lower than that in mother liver, which was consistent with basal metabolic activity. Unexpectedly, compared with basal metabolism in fetal liver, exposure to RTS during middle and late pregnancy caused an opposite gender difference in RTS metabolism and CYP3A expression in fetal liver. For the first time, our study proved that RTS was capable of permeating placenta barrier and entering fetal circulation, while the intrauterine pyrrolic metabolite was mainly generated by fetal liver, but not transported from mother circulation. Induction of CYP3A by RTS was gender-dependent in fetal liver, which was probably responsible for RTS-induced fetal

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Section: Discussionmentioning

confidence: 78%

Maternal-Fetal Disposition and Metabolism of Retrorsine in Pregnant Rats

Yang

Xiang

et al. 2018

Drug Metab Dispos

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“…that produce these types of toxins [ 44 ] does not overlap with the distribution of the loss of OCT1 activity, this substrate is proof of principle that lack of OCT1 activity could protect against ingested toxins. Furthermore, several other hepatotoxic alkaloids were recently reported to be OCT1 substrates [ 45 , 46 ]. Alternatively, Oct1 deficiency in mice was reported to protect from hepatic steatosis [ 1 ] and therefore may improve fitness.…”

Section: Discussionmentioning

confidence: 99%

Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1

Seitz¹,

Stalmann²,

Dalila³

et al. 2015

Genome Med

181

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BackgroundThe organic cation transporter OCT1 (SLC22A1) mediates the uptake of vitamin B1, cationic drugs, and xenobiotics into hepatocytes. Nine percent of Caucasians lack or have very low OCT1 activity due to loss-of-function polymorphisms in OCT1 gene. Here we analyzed the global genetic variability in OCT1 to estimate the therapeutic relevance of OCT1 polymorphisms in populations beyond Caucasians and to identify evolutionary patterns of the common loss of OCT1 activity in humans.MethodsWe applied massively parallel sequencing to screen for coding polymorphisms in 1,079 unrelated individuals from 53 populations worldwide. The obtained data was combined with the existing 1000 Genomes data comprising an additional 1,092 individuals from 14 populations. The identified OCT1 variants were characterized in vitro regarding their cellular localization and their ability to transport 10 known OCT1 substrates. Both the population genetics data and transport data were used in tandem to generate a world map of loss of OCT1 activity.ResultsWe identified 16 amino acid substitutions potentially causing loss of OCT1 function and analyzed them together with five amino acid substitutions that were not expected to affect OCT1 function. The variants constituted 16 major alleles and 14 sub-alleles. Six major alleles showed improper subcellular localization leading to substrate-wide loss in activity. Five major alleles showed correct subcellular localization, but substrate-specific loss of activity. Striking differences were observed in the frequency of loss of OCT1 activity worldwide. While most East Asian and Oceanian individuals had completely functional OCT1, 80 % of native South American Indians lacked functional OCT1 alleles. In East Asia and Oceania the average nucleotide diversity of the loss-of-function variants was much lower than that of the variants that do not affect OCT1 function (ratio of 0.03) and was significantly lower than the theoretically expected heterozygosity (Tajima’s D = −1.64, P < 0.01).ConclusionsComprehensive genetic analyses showed strong global variations in the frequency of loss of OCT1 activity with selection pressure for maintaining OCT1 activity in East Asia and Oceania. These results not only enable pharmacogenetically-based optimization of drug treatment worldwide, but may help elucidate the functional role of human OCT1.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0172-0) contains supplementary material, which is available to authorized users.

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“…MDCK-hCYP3A4 cells were also established in our laboratory [19], HepG2 cell line was obtained from the Institute of Biochemistry and Cell Biology (Shanghai, China). Dulbecco's modified eagle's medium (DMEM) and fetal bovine serum were purchased from Gibco BRL (Grand Island, NY, USA).…”

Section: Methodsmentioning

confidence: 99%