Acetaminophen

Synthesized oligonucleotides were obtained from Integrated DNA Technologies (Coralville, IA).
Coumarin, phenacetin, 7-hydroxyCoumarin, and acetaminophen were obtained from Fujifilm Wako Pure Chemicals (Osaka, Japan). Pooled liver microsomes of humans (75 males and 75 females), 3 male and 3 female dogs, and 3 male and 3 female minipigs were purchased from Corning Life Sciences (Woburn, MA). Liver microsomes were prepared from two tree shrews as described previously (Yamazaki et al., 2014; Uno et al., 2022a; Uno et al., 2022c) . Recombinant human CYP2A6 and CYP2A13 in bacterial membranes were prepared using the bicistronic protein expression system with human NADPH-P450 reductase as described previously (Shimada et al., 1997; Uehara et al., 2015; Uno et al., 2006; Uno et al., 2022a; Uno et al., 2022c) . All other reagents were purchased from Sigma-Aldrich or Fujifilm Wako Pure Chemicals, unless otherwise specified.

Materials Twenty-two compounds: acetaminophen, azathioprine, caffeine, chloramphenicol, chlorpheniramine maleate salt, colchicine, cromolyn sodium, dextromethorphan hydrobromide monohydrate, diphenhydramine hydrochloride, diphenidol hydrochloride, erythromycin, famotidine, flufenamic acid, haloperidol, hydrocortisone, methimazole, noscapine, ofloxacin, papaverine hydrochloride, propylthiouracil, quinine hydrochloride and strychnine nitrate were purchased from Wako Pure Chemical Industries, Ltd., Osaka, Japan.

All animal experiments were performed under the supervision and with the approval of the Institutional Animal Care and Use Committee of Hokkaido University, Japan (approval number 14-0119), which conform to the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).
Chemicals. 1-Hydroxypyrene, pyrene glucuronide, Acetaminophen glucuronide, β-estradiol, sodium cholate hydrate, UDPGA, and RNA later ® were obtained from Sigma-Aldrich (St.
Louis, MO). Acetaminophen, acetic acid, sodium phosphate, and ammonium acetate solution were purchased from Wako Pure Chemical Industries Ltd. (Osaka, Japan). β-estradiol-3-β-Dglucuronide sodium salt was obtained from Santa-Cruz Biotechnology Inc. (Santa-Cruz, CA).
All chemicals used for high-performance liquid chromatography (HPLC) and mass spectrometry (MS) were HPLC or MS grade and were obtained from Kanto Chemical Co. Inc.
(Tokyo, Japan).