27Citreoviridin (CIT) produced by Penicillium citreonigrum as a secondary metabolite is a 28 yellow rice toxin that has been reported to be related to acute cardiac beriberi; however, its 29 toxicokinetics remain unclear. The present study elucidated the toxicokinetics through swine 30 in vivo experiments and predicted the human toxicokinetics by a comparison with findings 31 from in vitro experiments. Swine in vivo experiments revealed that CIT had a high 32 bioavailability of more than 90%. In addition, it showed a large volume of distribution (1.005 33 ± 0.195 L/kg) and long elimination half-life (17.7 ± 3.3 h) in intravenous. These results
34suggested the possibility of a slow metabolism of CIT. An intestinal permeability study using 35 the human cell line Caco-2 showed that CIT had a high permeability coefficient, suggesting it 36 would be easily absorbed in human intestine, similar to its absorption in swine. The 37 metabolite profiles were investigated by incubating CIT with S9 obtained from swine and 38 humans. Hydroxylation, methylation, desaturation and dihydroxylation derivatives were 39 detected as the predominant metabolites, and CIT glucuronide was produced slowly 40 compared with above metabolites. A comparison of the peak area ratios obtained using 41 quadrupole time-of-flight mass spectrometer showed that the rates of all of the main 42 metabolites except for glucuronide produced using human S9 were three-fold higher than 3 43 those obtained using swine S9. Furthermore, the elimination of CIT using human S9 was 44 more rapid than when using swine S9, indicating that CIT would be metabolized faster in 45 humans than in swine. These in vivo results suggested that CIT is easily absorbed in swine 46 and persists in the body for a long duration. Furthermore, the CIT metabolism appeared to be 47 faster in human liver than in swine liver in vitro, although the bioavailability of CIT was 48 predicted to be similarly high in humans as in swine. 49 4 50 Introduction 51 Citreoviridin (CIT) is a mycotoxin produced by Penicillium citreonigrum, Aspergillus terreus 52 and Eupenicillium ochrosalmoneum as a secondary metabolite [1]. Because CIT is mainly 53 found as a contaminant in rice, it is a serious problem in countries where people consume rice 54 as a staple food. 55 In 2006, an outbreak of beriberi occurred in Brazil, with a reported 40 of 1207 cases 56 dying [2]. Since P. citreonigrum and CIT were detected in rice samples, it was suspected that 57 rice was the causative food of beriberi in the area [3]. CIT contaminating yellow rice has 58 been reported to be related to acute cardiac beriberi (so-called "Shoshin-kakke") [4]. 59 Uraguchi et al. discovered that an ethanol extract from rice infected with P. citreo-viride 60 Biourge (current P. citreonigrum) caused symptoms in mice similar to acute cardiac beriberi 61 in humans. In addition, Ueno et al. reported that the isolate from P. citreo-viride BIourge 62 which was isolated by Sakabe et al. was chemically identical with CIT [4][5]. Although 63 "Shoshin...