CYP4F Enzymes Are Responsible for the Elimination of Fingolimod (FTY720), a Novel Treatment of Relapsing Multiple Sclerosis

Jin, Yi; Zollinger, Markus; Borell, Hubert; Zimmerlin, Alfred; Patten, Christopher

doi:10.1124/dmd.110.035378

Cited by 58 publications

(47 citation statements)

References 33 publications

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“…Its elimination occurs primarily by hydroxylation mediated by CYP4F2 and possibly other enzymes of the CYP4F subfamily. Although -hydroxylated fingolimod was the major biotransformation product observed, six other metabolites with internal hydroxylations were identified (53). This goes along with our identification of multiple isomers of both 1-deoxySO-OH and 1-deoxySA-2OH.…”

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4fsupporting

confidence: 53%

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Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org Sphingolipid (SL) de novo synthesis typically starts with the condensation of serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) (1-3). SPT can also use alanine in certain conditions (4), which results in the formation of the atypical cytotoxic 1-deoxysphingolipids (1-deoxySLs). These lack the C1-hydroxyl group of regular SLs, which is essential for further metabolic steps and degradation (4, 5). As such, 1-deoxySLs are commonly believed to be "dead-end" metabolites that accumulate within cells, tissues, and body fluids.Pathologically elevated 1-deoxySLs have been found in a number of neurological and metabolic disorders. They are a hallmark of hereditary sensory autonomic neuropathy type 1 (HSAN1), a rare autosomal dominant inherited peripheral neuropathy that is caused by various mutations in SPT. Plasma 1-deoxySLs are also elevated in patients with nondiabetic metabolic syndrome (MetS) and T2D (6) and may contribute to the development of diabetic sensory polyneuropathy (DSN), which is clinically very similar to HSAN1 (7,8). Both conditions start in the lower extremities with a loss of sensation often accompanied by positive sensory symptoms such as hyperpathia and neuropathic pain, as well as the development of painless wounds leading to ulcers (9, 10). L-serine supplementation was shown to effectively lower 1-deoxySL levels while improving Abstract The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic -cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D. (I.A., A.O., T.H., and A.v.E.) Abbreviations: ATRA, all-trans retinoic acid; CYP, cytochrome P450; DB, double bond; 1-deoxySA, 1-deoxysphinganine; 1-deoxySAdiene, deoxysphingadiene; 1-deoxySA-OH, hydroxyl-deoxysphinganine; 1-deoxySA-2OH, dihydroxyl-deoxysphinganine; 1-deoxySL, 1-deoxysphingolipid; 1-deoxySO, 1-deoxysphingosi...

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Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4fsupporting

confidence: 53%

“…CYP4F enzymes have been shown to mediate the degradation of fingolimod (FTY720), an S1P analog used in treating relapsing multiple sclerosis (53). Its elimination occurs primarily by hydroxylation mediated by CYP4F2 and possibly other enzymes of the CYP4F subfamily.…”

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4fmentioning

confidence: 99%

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

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“…In addition, P450 4F12 reportedly metabolizes a number of antiallergy drugs, including ebastine, astemizole, and terfenadine (Hashizume et al, 2002;Eksterowicz et al, 2014). P450 4F2 and/or 4F3B also are responsible for the O-demethylation of the antiparasitic prodrug pafuramidine and the v-hydroxylation of fingolimod, an oral drug for relapsing multiple sclerosis (Wang et al, 2007;Jin et al, 2011). These findings suggest that P450 4F enzymes are responsible for endogenous and xenobiotic biotransformations.…”

Section: Introductionmentioning

confidence: 78%

“…Indeed, O-demethylation of pafuramidine in human intestine microsomes reportedly inhibited 92% of total metabolic activity by anti-P450 4F2 antibodies, whereas the antibodies against P450 3A4/5 and 2J2 showed moderate inhibition (approximately 28%). In addition, P450 4F2 and/or 4F3B enzymes reportedly catalyzed v-hydroxylation of fingolimod, the major elimination pathway (Jin et al, 2011). v-Hydroxylation of fingolimod in human liver microsomes also inhibited 93% of total metabolic activity by anti-P450 4F2 antibodies, differing from little or no effects by antibodies of P450 2D6, 2E1, and 3A4.…”

Section: Discussionmentioning

confidence: 99%

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine

Uehara

Uno

Yuki

et al. 2016

Drug Metabolism and Disposition

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Common marmosets (Callithrix jacchus) are attracting attention as animal models in preclinical studies for drug development. However, cytochrome P450s (P450s), major drug-metabolizing enzymes, have not been fully identified and characterized in marmosets. In this study, based on the four novel P450 4F genes found on the marmoset genome, we successfully isolated P450 4F2, 4F3B, 4F11, and 4F12 cDNAs in marmoset livers. Deduced amino acid sequences of the four marmoset P450 4F forms exhibited high sequence identities (87%-93%) to the human and cynomolgus monkey P450 4F homologs. Marmoset P450 4F3B and 4F11 mRNAs were predominantly expressed in livers, whereas marmoset P450 4F2 and 4F12 mRNAs were highly expressed in small intestines and livers. Four marmoset P450 4F proteins heterologously expressed in Escherichia coli catalyzed the v-hydroxylation of leukotriene B 4 . In addition, marmoset P450 4F12 effectively catalyzed the hydroxylation of antiallergy drug ebastine, a human P450 2J/4F probe substrate. Ebastine hydroxylation activities by small intestine and liver microsomes from marmosets and cynomolgus monkeys showed greatly higher values than those of humans. Ebastine hydroxylation activities by marmoset and cynomolgus monkey small intestine microsomes were inhibited (approximately 60%) by anti-P450 4F antibodies, unlike human small intestine microsomes, suggesting that contribution of P450 4F enzymes for ebastine hydroxylation in the small intestine might be different between marmosets/ cynomolgus monkeys and humans. These results indicated that marmoset P450 4F2, 4F3B, 4F11, and 4F12 were expressed in livers and/or small intestines and were functional in the metabolism of endogenous and exogenous compounds, similar to those of cynomolgus monkeys and humans.

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“…In vitro studies with human liver microsomes and animal studies have shown that cytochrome P450 (CYP) 4F2 and other enzymes of the CYP4F subfamily, with a minor contribution reported from other CYP enzymes, are largely responsible for the oxidative metabolism and the subsequent elimination of FTY (Jin et al., 2011; Kalsotra, Anakk, Boehme, & Strobel, 2002; Kovarik et al., 2005, 2006; Wang & Strobel, 1997; Waxman, Ram, Pampori, & Shapiro, 1995; Zimmerlin & Patten, 2000). Sex‐dependent expression of cytochromes P450 and their influence on drug metabolism and drug toxicity have been previously reported.…”

Section: Resultsmentioning

confidence: 99%

Gender differences in safety issues during Fingolimod therapy: Evidence from a real‐life Relapsing Multiple Sclerosis cohort

et al. 2017

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ObjectiveBenefits and risks of new therapies in Multiple Sclerosis (MS) must be balanced carefully and tailored to patients. We aimed to describe our experience with Fingolimod (FTY), correlating demographics, clinical and hematological features of the Relapsing MS (RMS) cohort with the occurring Adverse Events (AEs).Material and MethodsPretreatment screening tests, cardiological observation, and safety follow‐up data were analyzed in 225 RMS patients. Changes in continuous data were analyzed post hoc with Wilcoxon ranks test; categorical variables were examined using McNemar test. Two‐way repeated‐measures analysis of variance (ANOVA) was used to analyze differences between baseline characteristic of the cohorts and Liver Function Tests (LFT) alterations. Binary logistic regression models were used to identify which of the baseline factors influenced LFT alterations and the occurrence of infections.ResultsDuring 2 years of follow‐up 24 patients (10%) interrupted FTY. Discontinuation most often was due to AEs (n = 14) or breakthrough disease (n = 5). The most frequently AEs were infections (10.6%). After the first year patients showing an infectious episode were mostly female (p = .04). The infections did not correlate with the decrease in white blood cells or to lymphocyte count. AST and ALT alterations were observed mostly in males (p = .002 and p = .01, respectively), and increase in GGT was reported in subjects older at FTY beginning (p < .05).ConclusionsFor a patient‐centered safety monitoring of FTY, we may apply gender‐specific warnings, for the detection of transaminases abnormalities and infectious episodes.

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CYP4F Enzymes Are Responsible for the Elimination of Fingolimod (FTY720), a Novel Treatment of Relapsing Multiple Sclerosis

Cited by 58 publications

References 33 publications

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine

Gender differences in safety issues during Fingolimod therapy: Evidence from a real‐life Relapsing Multiple Sclerosis cohort

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