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Peroxisome Proliferator-Activated Receptor Α Agonist-Induced Histidine Decarboxylase Gene Expression in the Rat and Mouse Liver

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Peroxisome Proliferator-Activated Receptor Α Agonist-Induced Histidine Decarboxylase Gene Expression in the Rat and Mouse Liver The Journal of Toxicological Sciences (J. Toxicol. Sci.) 475 Vol.45, No.8, 475-492, 2020 Original Article Peroxisome proliferator-activated receptor α agonist-induced histidine decarboxylase gene expression in the rat and mouse liver Yoko Amagase*, Yumiko Mizukawa* and Tetsuro Urushidani Department of Pathophysiology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan (Received September 4, 2019; Accepted May 15, 2020) ABSTRACT — By analysis of the data from the Toxicogenomics Database (TG-GATEs), histidine decarboxylase gene (Hdc) was identified as largely and commonly upregulated by three fibrates, clofi- brate, fenofibrate, and WY-14,643, which are known to induce hepatocellular hypertrophy and prolifera- tion via stimulation of peroxisome proliferator-activated receptor α (PPARα) in rodents. As histamine has been reported to be involved in the proliferation of liver cells, the present study was conducted to focus on Hdc. Among other genes related to histidine and histamine, the expression of the gene of histamine ammonia lyase (Hal) was exclusively mobilized by the three fibrates. The expression of Hdc, which was usually very low in the liver, was increased with the repeated administration of fibrates, and concomitant- ly, the constitutive expression of Hal was suppressed. An interpretation is that the formation of urocanic acid from histidine under the normal condition switches to the formation of histamine. The mobilization of gene expression of Hdc and Hal by PPARα agonists could not be reproduced in primary cultured hepa- tocytes. The Hdc mRNA appeared to be translated to a protein which is processed differently from brain but similarly to gastric mucosa. Surprisingly, the fibrates caused hepatic hypertrophy but no induction of Hdc mRNA at all in mice. These results revealed that the changes in the histidine catabolism by PPARα agonists might be partially, but not directly, involved in the hepatocyte proliferation in rats, and there is a large genetic distance even between rat and mouse. Key words: Toxicogenomics, Transcriptome database, Species difference, Fibric acid, Histidine decarboxylase INTRODUCTION of the key causal genes (Gonzalez and Shah, 2008). Our analysis of the data in the Toxicogenomics Data- Peroxisome proliferator-activated receptor α (PPARα) base (TG-GATEs) in the previous study (Mizukawa et al., agonists are the first-choice drugs for dyslipidemic 2020) proposed a list of genes that are reproducibly and patients with high triglyceride. Their repeated administra- markedly upregulated by PPARα agonists. We suggested tion to rodents, however, certainly causes hepatic hyper- in the study that a) some important changes may occur trophy within a few days and thereafter hepatic tumor in before the elevation of c-Myc, b) various genes, which a high incidence following long-term administration. This are scarcely related to lipid metabolism, are upregulat- toxicity has been considered rodent-specific and therefore ed together with that related to lipid metabolism and to considered to be no risk in humans (Desvergne and Wahli, cell proliferation, c) many of the genes unrelated to lip- 1999; Han et al., 2017). Hepatic hypertrophy as well as id metabolism are not induced in the primary cultured tumor has been attributed to PPARα by analysis of knock- hepatocytes, and d) the gene list might contain genes that out mice (Lee et al., 1995) and thus the species differ- are involved in the rodent-specific hepatotoxicity. Among ence occurs in the reaction after the step of PPARα acti- them, we pay attention to histidine decarboxylase gene vation, but its detailed mechanism is unknown, although (Hdc), which was highly upregulated by PPARα agonists the upregulation of c-Myc has been suggested to be one and is physiologically interesting. Correspondence: Tetsuro Urushidani (E-mail: [email protected]) *These authors equally contributed to this work. Vol. 45 No. 8 476 Y. Amagase et al. Histidine decarboxylase (HDC) is the only enzyme together with the other drugs, middle dose data were used synthesizing histamine, and is usually quite low in adult instead. During the project, it sometimes occurred that tissues except mast cells, gastric ECL cells, or basophils, gene expression changes in single dose were so small that where HDC is constitutively expressed and histamine is even the highest dose showed almost the same results as stored in the secretory vesicles (Ichikawa et al., 2010). control vehicle, and then additional experiments were per- HDC is enriched in some developing organs, and the liv- formed employing higher dose(s). In two cases (CPZ and er is the most enriched organ in the rat fetus (Taguchi et ADP) among them, the low dose was omitted and indi- al., 1984). HDC activity is markedly induced in the liv- cated as NA in the table. They are basically aligned as the er, lung, or spleen under pathophysiological conditions order of the project number but the drugs with high ago- where various cytokines are involved (Endo et al., 1986). nistic potency of PPARα are dispersed in order to avoid Histamine produced by induced HDC is reported to play the overlapping of the symbols on the 3D-graph. a role in cell proliferation, such as in vascular smooth The concentrations of the drugs for primary cultured muscle cells during restenosis of coronary artery (Fang et hepatocytes were independently determined by a pilot test al., 2005) and various cancer types (Blaya et al., 2010; for cellular toxicity. The highest concentration was set to Medina and Rivera, 2010). It is also reported that HDC 10–20% of the lethal concentration as estimated by lac- is induced in the liver by partial hepatectomy (Ishikawa tate dehydrogenase leakage over 24 hr. When the cells et al., 1970; Chang et al., 2010), which markedly stimu- could tolerate as much as 10 mM or the level equal to lates hepatic cell proliferation. Consequently, we consider the solubility limit of the compound in DMSO (allowed it to be highly possible that induction of Hdc is involved to add up to 0.1% in the final concentration), the highest in hepatic hypertrophy caused by PPARα agonists. concentration was set to either value. In general, the max- imum concentration (high) was decreased by a factor of 5 MATERIALS AND METHODS to middle and low concentration (Table 1). The precise protocols for TG-GATEs are also availa- Gene expression data in the database ble from the same web page. In general, for in vivo pro- Transcriptome data of 132 chemicals, body weight and tocol, 7-week-old male Sprague Dawley (SD) rats were liver weight changes were obtained from the database, treated with three doses of each test drug (low, middle, TG-GATEs (http://toxico.nibiohn.go.jp/) (Urushidani, high, and vehicle: 5 rats each) and sacrificed 3, 6, 9, and 2008). The doses, the vehicles, and the abbreviations for 24 hr after single oral dosing as well as 24 hr after repeat- the 132 drugs analyzed in the present study are summa- ed dosing for 3, 7, 14, and 28 days. Toxicology data were rized in Table 1. Most of the drugs were dissolved or sus- obtained from 5 animals while gene expression analysis pended in 0.5% methylcellulose (MC) or corn oil and by Affymetrix GeneChip (Rat Expression Array 230 2.0) administered orally. In some cases indicated as “saline” in was performed for 3 out of 5. As for in vitro protocol, iso- the column for vehicle, the drug was dosed by intravenous lated hepatocytes from 7 weeks SD rats according to the injection. Ethanol was diluted with distilled water. The standard method were cultivated with a collagen coated highest dose of each drug for repeated administration was six-well plate for 24 hr, and 2, 8, and 24 hr after the addi- first determined by a small-scale dose finding test (repeat- tion of the test drug (low, middle, high, and vehicle: 2 ed administration for 1 week) such that the expected sur- wells each) and the cells were harvested and analyzed for vival of the animals until the end of 28 days of repeated gene expression (Tamura et al., 2006). administration was set as the first priority. In general, the The digital image files were processed by Affymetrix highest dose was reduced by the factor of the square root Microarray Suite version 5.0 and the intensities were nor- of 10, to middle and to low dose, and the same dose lev- malized for each chip by setting the mean intensity to 500 el was employed for the single dosing. When the toxicity (per chip normalization). was expected to be highly increased in repeated adminis- tration in advance, like in anti-inflammatory, anti-cancer, Additional experiments in the present study or immunosuppressive drugs, higher dose levels were For the data newly added by the present study, male employed for single dose experiments such that at least 6-week-old SD rats and C57BL/6N mice were purchased one dose level was common with the repeated dosing. In from Shimizu Laboratory Supplies Co. and used after one some cases, because of the death or early sacrifice when week of acclimatization. The experimental protocol was moribund, the animals for high dose at 28 days were approved by The Animal Research Committee in Doshi- lacking and this is indicated with parentheses in Table 1. sha Women’s College of Liberal Arts. When the high dose data of these drugs were presented In order to see the reproducibility of the data in TG- Vol. 45 No. 8 477 PPARα-induced HDC gene expression in the rat and mouse liver Table 1. List of the drugs stored in “TG-GATEs”,
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