Embryonic Arrhythmia by Inhibition of HERG Channels: A Common Hypoxia-related Teratogenic Mechanism for Antiepileptic Drugs?
Faranak Azarbayjani,
Bengt R. Danielsson,
Faranak Azarbayjani
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala; and
Search for more papers by this authorBengt R. Danielsson
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala; and
AstraZeneca R&D, Safety Assessment, Södertälje, Sweden
Search for more papers by this authorFaranak Azarbayjani,
Bengt R. Danielsson,
Faranak Azarbayjani
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala; and
Search for more papers by this authorBengt R. Danielsson
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala; and
AstraZeneca R&D, Safety Assessment, Södertälje, Sweden
Search for more papers by this authorAddress correspondence and reprint requests to Prof. B. Danielsson at AstraZeneca R & D Södertälje, Safety Assessment, S-151 85 Södertälje, Sweden. E-mail: [email protected]
Abstract
Summary: Purpose: There is evidence that drug-induced embryonic arrhythmia initiates phenytoin (PHT) teratogenicity. The arrhythmia, which links to the potential of PHT to inhibit a specific potassium channel (Ikr), may result in episodes of embryonic ischemia and generation of reactive oxygen species (ROS) at reperfusion. This study sought to determine whether the proposed mechanism might be relevant for the teratogenic antiepileptic drug trimethadione (TMO).
Methods: Effects on embryonic heart rhythm during various stages of organogenesis were examined in CD-1 mice after maternal administration (125–1,000 mg/kg) of dimethadione (DMO), the pharmacologically active metabolite of TMO. Palatal development was examined after administration of a teratogenic dose of DMO and after simultaneous treatment with DMO and a ROS-capturing agent (α-phenyl-N-tert-butyl-nitrone; PBN). The Ikr blocking potentials of TMO and DMO were investigated in HERG-transfected cells by using voltage patch-clamping tests.
Results: DMO caused stage-specific (gestation days 9–13 only) and dose-dependent embryonic bradycardia and arrhythmia at clinically relevant maternal plasma concentrations (3–11 mM). Hemorrhage in the nasopharyngeal part of the embryonic palate (within 24 h) preceded cleft palate in fetuses at term. Simultaneous treatment with PBN significantly reduced the incidence of DMO-induced cleft palate, from 40 to 13%. Voltage patch-clamping studies showed that particularly DMO (70% inhibition), but also TMO, had Ikr blocking potential at clinically relevant concentrations.
Conclusions: TMO teratogenicity, in the same way as previously shown for PHT, was associated with Ikr-mediated episodes of embryonic cardiac arrhythmia and hypoxia/reoxygenation damage.
REFERENCES
- 1 Finnell RH, Dansky LV. Parental epilepsy. anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades, 1: Animal studies. Reprod Toxicol 1991; 5: 281–99.
- 2 Briggs GG, Freeman RK, Yaffe SJ. Carbamazepine, phenytoin, trimethadione. In: CW Mitchell, ed. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Baltimore: Williams & Wilkins, 1998: 139, 859, 866, 1058–143.
- 3 Brown NA, Shull G, Fabro S. Assessment of the teratogenic potential of trimethadione in the CD-1 mouse. Toxicol Appl Pharmacol 1979; 51: 59–71.
- 4 Martz F, Failinger C, Blake DA. Phenytoin teratogenesis: correlation between embryopathic effect and covalent binding of putative arene oxide metabolite in gestational tissue. J Pharmacol Exp Ther 1977; 203: 231–9.
- 5 Lindhout D. Metabolic interactions in clinical and experimental teratogenesis. In: H Nau, WJ Scott, eds. Pharmacokinetics in Teratogenesis. Boca Raton: CRC Press, 1987: 233–50.
- 6 Danielsson BR, Sköld AC, Azarbayjani F. Class III antiarrhythmics and phenytoin: teratogenicity due to embryonic cardiac dysrhythmia and reoxygeneration damage. Curr Pharm Design 2001; 7: 787–802.
- 7 Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990; 42: 223–86.
- 8 Nobile M, Vercellino P. Inhibition of delayed rectifier K+ channels by phenytoin in rat neuroblastoma cells. Br J Pharmacol 1997; 120: 647–52.
- 9 Warmke JW, Ganetzky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A 1994; 91: 3438–42.
- 10 Davies MP, An RH, Doevendans P, et al. Developmental changes in ionic channel activity in the embryonic murine heart. Circ Res 1996; 78: 15–25.
- 11 Abrahamsson C, Palmer M, Ljung B, et al. Induction of rhythm abnormalities in the fetal rat heart: a tentative mechanism for the embryotoxic effect of the class III antiarrhythmic agent almokalant. Cardiovasc Res 1994; 28: 337–44.
- 12
Webster WS,
Brown-Woodman PD,
Snow MD, et al. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity.
Teratology
1996; 53: 168–75.DOI: 10.1002/(sici)1096-9926(199603)53:3<168::aid-tera4>3.0.co;2-0
10.1002/(sici)1096-9926(199603)53:3<168::aid-tera4>3.0.co;2-0 CAS PubMed Web of Science® Google Scholar
- 13 Brent RL, Franklin JB. Uterine vascular clamping: new procedure for the study of congenital malformations. Science 1960; 132: 89–91.
- 14 Leist KH, Grauwiler J. Fetal pathology in rats following uterine-vessel clamping on day 14 of gestation. Teratology 1974; 10: 55–67.
- 15 Viskin S. Long QT syndromes and torsade de pointes. Lancet 1999; 354: 1625–33.
- 16 Doig JC. Drug-induced cardiac arrhythmias: incidence, prevention and management. Drug Safety 1997; 17: 265–75.
- 17 Tomson T, Kennebäck G. Arrhythmia, heart rate variability, and antiepileptic drugs. Epilepsia 1997; 38: S48–51.
- 18 Thueson DO, Withrow CD, Giam CS, et al. Uptake, distribution, metabolism, and excretion of trimethadione in rats. Epilepsia 1974; 15: 563–78.
- 19 Butler TC. Quantitative studies of the demethylation of trimethadione (Tridione). J Pharmacol Exp Ther 1953; 108: 11–7.
- 20 Butler TC, Kuroiwa Y, Waddell WJ, et al. Effects of 5,5-dimethyl-2,4-oxazolidinedione (DMO) on acid-base and electrolyte equilibria. J Pharmacol Exp Ther 1966; 152: 62–6.
- 21 Booker HE. Trimethadione and other oxazolidinediones: relation of plasma levels to clinical control. In: DM Woodbury, JK Penry, RD Schmidt, eds. Antiepileptic drugs. New York: Raven Press, 1972: 403–7.
- 22 Wells PG, Nagai MK, Greco GS. Inhibition of trimethadione and dimethadione teratogenicity by the cyclooxygenase inhibitor acetylsalicylic acid: a unifying hypothesis for the teratologic effects of hydantoin anticonvulsants and structurally related compounds. Toxicol Appl Pharmacol 1989; 97: 406–14.
- 23 Buttar HS, Dupuis I, Khera KS. Dimethadione-induced fetotoxicity in rats. Toxicology 1978; 9: 155–64.
- 24 Midha KK, Buttar HS, Rowe M, et al. Metabolism and disposition of trimethadione in pregnant rats. Epilepsia 1979; 20: 417–23.
- 25 Wellfelt K, Sköld AC, Wallin A, et al. Teratogenicity of the class III antiarrhythmic drug almokalant: role of hypoxia and reactive oxygen species. Reprod Toxicol 1999; 13: 93–101.
- 26 Chen G, Griffin M, Poyer JL, et al. HPLC procedure for the pharmacokinetic study of the spin-trapping agent, alpha-phenyl-N-tert-butyl nitrone (PBN). Free Radic Biol Med 1990; 9: 93–8.
- 27
Azarbayjani F,
Danielsson BR.
Pharmacologically induced embryonic dysrhythmia and episodes of hypoxia followed by reoxygenation: a common teratogenic mechanism for antiepileptic drugs?
Teratology
1998; 57: 117–26.DOI: 10.1002/(sici)1096-9926(199803)57:3<117::aid-tera1>3.3.co;2-#
10.1002/(SICI)1096-9926(199803)57:3<117::AID-TERA1>3.0.CO;2-Y CAS PubMed Web of Science® Google Scholar
- 28 Azarbayjani F, Danielsson BR. Phenytoin-induced cleft palate: evidence for embryonic cardiac bradyarrhythmia due to inhibition of delayed rectifier K+ channels resulting in hypoxia-reoxygenation damage. Teratology 2001; 63: 152–60.DOI: 10.1002/tera.1026
- 29
Danielsson BR,
Azarbayjani F,
Sköld AC, et al. Initiation of phenytoin teratogenesis: pharmacologically induced embryonic bradycardia and arrhythmia resulting in hypoxia and possible free radical damage at reoxygenation.
Teratology
1997; 56: 271–81.DOI: 10.1002/(sici)1096-9926(199710)56:4<271::aid-tera6>3.0.co;2-1
10.1002/(sici)1096-9926(199710)56:4<271::aid-tera6>3.0.co;2-1 CAS PubMed Web of Science® Google Scholar
- 30 Gazdzik WR, Filipek M, Kmiotek W. Rapid and simple HPLC determination of 5,5-dimethyl-2,4-oxazolidynedione in rabbit serum. Biomed Chromatogr 1987; 2: 137–8.
- 31 Mattson RH, Petroff OA, Rothman D, et al. Vigabatrin: effect on brain GABA levels measured by nuclear magnetic resonance spectroscopy. Acta Neurol Scand 1995;( suppl 162): 27–30.
- 32 Carlsson L, Amos GJ, Andersson B, et al. Electrophysiological characterization of the prokinetic agents cisapride and mosapride in vivo and in vitro: implications for proarrhythmic potential? J Pharmacol Exp Ther 1997; 282: 220–7.
- 33 German J, Kowal A, Ehlers KH. Trimethadione and human teratogenesis. Teratology 1970; 3: 349–62.
- 34 Nichols MM. Fetal anomalies following maternal trimethadione ingestion. J Pediatr 1973; 82: 885–6.
- 35 Zackai EH, Mellman WJ, Neiderer B, et al. The fetal trimethadione syndrome. J Pediatr 1975; 87: 280–4.
- 36 Feldman GL, Weaver DD, Lovrien EW. The fetal trimethadione syndrome: report of an additional family and further delineation of this syndrome. Am J Dis Child 1977; 131: 1389–92.
- 37 Zellweger H. Anticonvulsants during pregnancy: a danger to the developing fetus? Clin Pediatr 1974; 13: 338–41.
- 38 Rischbieth RH. Troxidone (trimethadione) embryopathy: case report with review of the literature. Clin Exp Neurol 1979; 16: 251–6.
- 39 Hanson JW. Teratogen update: fetal hydantoin effects. Teratology 1986; 33: 349–53.
- 40 Hetzel S, Brown KS. Facial clefts and lip hematomas in mouse in mouse fetuses given diphenylhydantoin [Abstract]. J Dent Res 1975; 54A: 83.
- 41 Petter C. DPH-induced macrocytosis in the 14-day rat foetus. Experientia 1979; 35: 1493–4.
- 42 Danielson MK, Danielsson BR, Marchner H, et al. Histopathological and hemodynamic studies supporting hypoxia and vascular disruption as explanation to phenytoin teratogenicity. Teratology 1992; 46: 485–97.
- 43 Franklin JB, Brent RL. The effect of uterine vascular clamping on the development of rat embryos three to fourteen days old. J Morphol 1964; 115: 273–90.
- 44 Leist KH, Grauwiler J. Influence of the developmental stage on embryotoxicity following uterine vessel clamping in the rat. European Teratology Society, Praha: 2nd Conference 1973;173–6.
- 45 Danielsson BR, Webster WS Cardiovascular active drugs. In:Kavlock RJ, Daston GP, eds. Drug toxicity in embryonic development II; advances in understanding mechanisms of birth defects: mechanistic understanding of human developmental toxicants. Berlin: Springer, 1997:161–90.
- 46 Vereecke J, Carmeliet E. The effect of external pH on the delayed rectifying K+ current in cardiac ventricular myocytes. Pflugers Arch Eur J Physiol 2000; 439: 739–51.
- 47 Gutteridge JM. Free radicals in disease processes: a compilation of cause and consequence. Free Radic Res Commun 1993; 19: 141–58.
- 48 McCord JM. Human disease, free radicals, and the oxidant/antioxidant balance. Clin Biochem 1993; 26: 351–7.
- 49 Kalyanaraman B, Konorev EA, Joseph J, et al. Is free radical generation an important component of ischemia/reperfusion injury? Redox Rep 1995; 1: 181–4.
- 50 Fantel AG, Person RE, Tumbic RW, et al. Studies of mitochondria in oxidative embryotoxicity. Teratology 1995; 52: 190–5.
- 51 Fantel AG, Mackler B, Stamps LD, et al. Reactive oxygen species and DNA oxidation in fetal rat tissues. Free Radic Biol Med 1998; 25: 95–103.
- 52 Yu WK, Wells PG. Evidence for lipoxygenase-catalyzed bioactivation of phenytoin to a teratogenic reactive intermediate: in vitro studies using linoleic acid-dependent soybean lipoxygenase, and in vivo studies using pregnant CD-1 mice. Toxicol Appl Pharmacol 1995; 131: 1–12.
- 53 Ban Y, Konishi R, Kawana K, et al. Embryotoxic effects of L-691,121, a class III antiarrhythmic agent, in rats. Arch Toxicol 1994; 69: 65–71.DOI: 10.1007/s002040050139
- 54 Spence SG, Vetter C, Hoe CM. Effects of the class III antiarrhythmic, dofetilide (UK-68,798) on the heart rate of midgestation rat embryos, in vitro. Teratology 1994; 49: 282–92.
- 55
Marks TA,
Terry RD.
Developmental toxicity of ibutilide fumarate in rats after oral administration.
Teratology
1996; 54: 157–64.
10.1002/(SICI)1096-9926(199609)54:3<157::AID-TERA6>3.0.CO;2-0 CAS PubMed Web of Science® Google Scholar
- 56 Webster WS, Lipson AH, Brown-Woodman PD. Uterine trauma and limb defects. Teratology 1987; 35: 253–60.
- 57 Mercier-Parot L, Tuchmann-Duplessis H. The dysmorphogenic potential of phenytoin: experimental observations. Drugs 1974; 8: 340–53.
- 58 Danielsson BR, Danielson K, Tomson T. Phenytoin causes phalangeal hypoplasia in the rabbit fetus at clinically relevant free plasma concentrations. Teratology 1995; 52: 252–9.
- 59 Danielsson BR, Danielson M, Rundqvist E, et al. Identical phalangeal defects induced by phenytoin and nifedipine suggest fetal hypoxia and vascular disruption behind phenytoin teratogenicity. Teratology 1992; 45: 247–58.
- 60 Collins MD, Fradkin R, Scott WJ. Induction of postaxial forelimb ectrodactyly with anticonvulsant agents in A/J mice. Teratology 1990; 41: 61–70.
- 61 Collins MD, Walling KM, Resnick E, et al. The effect of administration time on malformations induced by three anticonvulsant agents in C57BL/6J mice with emphasis on forelimb ectrodactyly. Teratology 1991; 44: 617–27.
- 62 Harbison RD, Becker BA. Diphenylhydantoin teratogenicity in rats. Toxicol Appl Pharmacol 1972; 22: 193–200.
- 63 Netzloff ML, Streiff RR, Frias JL, et al. Folate antagonism following teratogenic exposure to diphenylhydantoin. Teratology 1979; 19: 45–9.
- 64 Sköld AC, Wellfelt K, Danielsson BR. Stage-specific skeletal and visceral defects of the IKr-blocker almokalant: further evidence for teratogenicity via a hypoxia-related mechanism. Teratology 2001; 64: 292–300.
- 65 Grabowski CT. Embryonic oxygen deficiency: a physiological approach to analysis of teratological mechanisms. In: DHM Woollam, ed. Advances in teratology. London: Logos Press, 1970: 125–69.
- 66 Hansen DK, Hodes ME. Comparative teratogenicity of phenytoin among several inbred strains of mice. Teratology 1983; 28: 175–9.
- 67 Hansen DK, Billings RE. Effect of route of administration on phenytoin teratogenicity in A/J mice. J Craniofac Genet Dev Biol 1986; 6: 131–8.
- 68 Vorhees CV. Fetal anticonvulsant syndrome in rats: dose- and period-response relationships of prenatal diphenylhydantoin, trimethadione and phenobarbital exposure on the structural and functional development of the offspring. J Pharmacol Exp Ther 1983; 227: 274–87.
- 69 Fantel AG, Barber CV, Mackler B. Ischemia/reperfusion: a new hypothesis for the developmental toxicity of cocaine. Teratology 1992; 46: 285–92.
- 70 Fantel AG, Barber CV, Carda MB, et al. Studies of the role of ischemia/reperfusion and superoxide anion radical production in the teratogenicity of cocaine. Teratology 1992; 46: 293–300.
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