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  • In summary the loss of seven Cyp a genes lead


    In summary, the loss of seven Cyp3a genes lead to sexual dimorphic changes during the eight weeks of high fat diet treatment with Cyp3a-null female mice showing a healthier acclimation to a high fat diet through decreased weight gain, higher adiponectin, lower B-OHB levels, and a better response to glucose; while the Cyp3a-null males succumb to increased fatty liver including slightly increased weight, higher hepatic polar lipids and triglycerides, and greater liver weight. Overall, the changes in HFD-induced health parameters in females are consistent with other studies showing that compounds that inhibit Cyp3a or perturb Cyp3a-mediated fatty formula for dilution metabolism protect from obesity [74,93], and the increases in weight in males are moderate. Correspondingly, PXR activation and subsequent CYP3A induction is associated with weight gain in females [39]. Ultimately, inhibition of CYP activity by environmental compounds or drugs may alter hepatic and non-hepatic lipid levels with different effects in males than females in which males may present increased steatosis and females show a mitigation of the effects of a HFD.
    Conflicts of interest
    Acknowledgements This work was supported by NIEHS grant R15ES017321.
    Introduction We have recently characterised the drug interaction potential of clementine juice in vitro, leading i.a. to both an increase in cytochrome P450 (CYP) 3A4 expression as well as a reduced CYP3A4 activity due to enzyme inhibition (Theile et al., 2017). The case of a 27-y-old female renal transplant patient with a functional kidney allograft and well-adjusted immunosuppression prompted us to this investigation, because she presented a 2.5-fold increase in tacrolimus concentration in whole blood, while consuming large amounts of clementines, thus suggesting a potential food-drug interaction. So far, no clinical drug interaction data have been reported for clementines or clementine juice. Only for mandarin juice a few reports indicate a lack of interaction with CYP3A4 substrates such as cyclosporine or midazolam (Sorkhi et al., 2007, Sorkhi et al., 2008; Backman et al., 2000). In contrast, for grapefruit juice containing furanocoumarins like bergamottin, which are not present in clementines or mandarins (Theile et al., 2017), interactions with drugs are known, including an increase of the bioavailability of tacrolimus (Liu et al., 2009; Peynaud et al., 2007). To assess the potential clinical relevance of the in vitro findings, we conducted two single case pilot experiments in the well-controlled environment of a clinical pharmacology trial unit and rechallenged the renal transplant patient with clementines a year later while monitoring CYP3A activity, tacrolimus pharmacokinetics, and serum creatinine. To substantiate the findings, one of the investigators conducted a self-experiment, by chronically exposing himself to clementine juice and repetitively phenotyping his CYP3A activity. Since the results obtained differed from those obtained in the earlier study, we quantified the flavonoids in the clementine juice by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) to clarify whether different flavonoid compositions might explain the discrepancies.
    Materials and methods
    Discussion Based on increased tacrolimus concentrations in a patient under clementine consumption and the in vitro drug interaction potential of the compounds present in clementines that may both induce and inhibit drug metabolising enzymes and drug transporters, we conducted two pilot experiments to test the clinical relevance of the in vitro findings, which had suggested a possible beverage/food-drug interaction. In contrast to the previously observed sharp rise of tacrolimus concentrations, we were unable to reproduce the effect of clementine ingestion on tacrolimus plasma concentrations in the same patient. The observed increase in tacrolimus Cmin (5.0 μg/L at −48 h, 6.1 μg/L at +48 h) and Cmax (11.9 μg/L at −48 h, 14.9 μg/L at 48 h) during clementine ingestion was within the range of normal intra-patient fluctuation (Park et al., 2007). The C/D ratio during our single case experiment ranged between 0.89 and 1.36 (Fig. 1).