Hepatic glucuronidation of tetrabromobisphenol A and tetrachlorobisphenol A: interspecies differences in humans and laboratory animals and responsible UDP-glucuronosyltransferase isoforms in humans.

Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA), bisphenol A (BPA) analogs, are endocrine-disrupting chemicals predominantly metabolized into glucuronides by UDP-glucuronosyltransferase (UGT) enzymes in humans and rats. In the present study, TBBPA and TCBPA glucuronidation by the liver microsomes of humans and laboratory animals (monkeys, dogs, minipigs, rats, mice, and hamsters) and recombinant human hepatic UGTs (10 isoforms) were examined. TBBPA glucuronidation by the liver microsomes followed the Michaelis-Menten model kinetics in humans, rats, and hamsters and the biphasic model in monkeys, dogs, minipigs, and mice. The CLint values based on the Eadie-Hofstee plots were mice (147) > monkeys (122) > minipigs (108) > humans (100) and rats (98) > dogs (81) > hamsters (47). TCBPA glucuronidation kinetics by the liver microsomes followed the biphasic model in all species except for minipigs, which followed the Michaelis-Menten model. The CLint values were monkeys (172) > rats (151) > mice (134) > minipigs (104), dogs (102), and humans (100) > hamsters (88). Among recombinant human UGTs examined, UGT1A1 and UGT1A9 showed higher TBBPA and TCBPA glucuronidation abilities. The kinetics of TBBPA and TCBPA glucuronidation followed the substrate inhibition model in UGT1A1 and the Michaelis-Menten model in UGT1A9. The CLint values were UGT1A1 (100) > UGT1A9 (42) for TBBPA glucuronidation and UGT1A1 (100) > UGT1A9 (53) for TCBPA glucuronidation, and the activities at high substrate concentration ranges were higher in UGT1A9 than in UGT1A1 for both TBBPA and TCBPA. These results suggest that the glucuronidation abilities toward TBBPA and TCBPA in the liver differ extensively across species, and that UGT1A1 and UGT1A9 expressed in the liver mainly contribute to the metabolism and detoxification of TBBPA and TCBPA in humans.

Species differences in activation of TRPA1 by resin additive-related chemicals relevant to indoor air quality.

Transient Receptor Potential Ankyrin 1 (TRPA1), which is expressed in the airways, has causative and exacerbating roles in respiratory diseases. TRPA1 is known as a target of sick building syndrome-related air pollutants, such as formaldehyde. Thus, an in vitro TRPA1 activation assay would be useful for predicting the potential risk of air pollution. In this study, we used human TRPA1 (hTRPA1)- and mouse TRPA1 (mTRPA1)-expressing cell lines to measure TRPA1 activation by the emerging indoor air pollutants 2-ethyl-1-hexanol (2-EH), a mixture of 2,2,4-trimethyl-1,3-pentanediol 1- and 3-monoisobutyrate (Texanol), and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB). The results indicated that 2-EH activated both hTRPA1 and mTRPA1 in a concentration-dependent manner, whereas TXIB did not activate hTRPA1 or mTRPA1. Texanol also activated hTRPA1 in a concentration-dependent manner. In contrast, a bell-shaped concentration-dependent curve was observed for mouse TRPA1 activation by Texanol, indicating inhibitory effects at a higher concentration range, which was also reported for menthol, a typical TRPA1 modulator. To further elucidate the mechanism underlying the species difference in TRPA1 activation by Texanol, V875G and G878V mutations were introduced into hTRPA1 and mTRPA1, respectively, which were reported to be key mutations for the inhibitory effect of menthol. These mutations switched the inhibitory effects of Texanol; thus, hTRPA1/V875G, but not mTRPA1/G878V, was inhibited at higher concentrations of Texanol. These results indicate that Texanol shares an interaction site with menthol. Overall, these findings suggest that careful interpretation is necessary when extrapolating rodent TRPA1-dependent toxicological effects to humans, especially with respect to the risk assessment of indoor air pollutants.

Hydrolysis of dibutyl phthalate and di(2-ethylhexyl) phthalate in human liver, small intestine, kidney, and lung: An in vitro analysis using organ subcellular fractions and recombinant carboxylesterases.

Phthalates are widely used plasticizers that are primarily and rapidly metabolized to monoester phthalates in mammals. In the present study, the hydrolysis of dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) in the human liver, small intestine, kidney, and lung was examined by the catalytic, kinetic, and inhibition analyses using organ microsomal and cytosolic fractions and recombinant carboxylesterases (CESs). The Vmax (y-intercept) values based on the Eadie-Hofstee plots of DBP hydrolysis were liver > small intestine > kidney > lung in microsomes, and liver > small intestine > lung > kidney in cytosol, respectively. The CLint values (x-intercept) were small intestine > liver > kidney > lung in both microsomes and cytosol. The Vmax and CLint or CLmax values of DEHP hydrolysis were small intestine > liver > kidney > lung in both microsomes and cytosol. Bis(4-nitrophenyl) phosphate (BNPP) effectively inhibited the activities of DBP and DEHP hydrolysis in the microsomes and cytosol of liver, small intestine, kidney, and lung. Although physostigmine also potently inhibited DBP and DEHP hydrolysis activities in both the microsomes and cytosol of the small intestine and kidney, the inhibitory effects in the liver and lung were weak. In recombinant CESs, the Vmax values of DBP hydrolysis were CES1 (CES1b, CES1c) > CES2, whereas the CLmax values were CES2 > CES1 (CES1b, CES1c). On the other hand, the Vmax and CLmax values of DEHP hydrolysis were CES2 > CES1 (CES1b, CES1c). These results suggest an extensive organ-dependence of DBP and DEHP hydrolysis due to CES expression, and that CESs are responsible for the metabolic activation of phthalates.

Species-Specific Activation of Transient Receptor Potential Ankyrin 1 by Phthalic Acid Monoesters.

Phthalic acid (PA) diesters are widely used in consumer products, as plasticizers, and are ubiquitous environmental pollutants. There is a growing concern about their adjuvant effect on allergic diseases. Although its precise mechanism remains unknown, possible involvement of transient receptor potential ankyrin 1 (TRPA1) has been suggested. Hence, in this study, the activation of human and mouse TRPA1s by a series of PA di- and monoesters was investigated using a heterologous expression system in vitro. Consequently, it was found that monoesters activated human TRPA1, where EC50 values were in the order of mono-hexyl > mono-heptyl > mono-n-octyl > mono-2-ethylhexyl > mono-isononyl and mono-isodecyl esters. Significant species differences in TRPA1 activation by PA monoesters were also discovered; PA monoesters activated human TRPA1 but not mouse TRPA1 in a concentration-dependent manner up to 50 µM. These findings suggest that PA esters may exert TRPA1-dependent adverse effects on humans, which have never been demonstrated in experimental animals.

Regioselective Glucuronidation of Flavones at C5, C7, and C4' Positions in Human Liver and Intestinal Microsomes: Comparison among Apigenin, Acacetin, and Genkwanin.

Flavones, which are distributed in a variety of plants and foods in nature, possess significant biological activities, including antitumor and anti-inflammatory effects, and are metabolized into glucuronides by uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) enzymes in humans. In this study, apigenin, acacetin, and genkwanin, flavones having hydroxyl groups at C5, C7, and/or C4'positions were focused on, and the regioselective glucuronidation in human liver and intestinal microsomes was examined. Two glucuronides (namely, AP-7G and AP-4'G for apigenin, AC-5G and AC-7G for acacetin, and GE-5G and GE-4'G for genkwanin) were formed from each flavone by liver and intestinal microsomes, except for only GE-4'G formation from genkwanin by intestinal microsomes. The order of total glucuronidation activities was liver microsomes > intestinal microsomes for apigenin and acacetin, and liver microsomes < intestinal microsomes for genkwanin. The order of CLint values (x-intercept) based on v versus V/[S] plots for apigenin glucuronidation was AP-7G > AP-4'G in liver microsomes and AP-7G < AP-4'G in intestinal microsomes. The order of CLint values was AC-5G < AC-7G for acacetin and GE-5G < GE-4'G genkwanin glucuronidation in both liver and intestinal microsomes. This suggests that the abilities and roles of UGT enzymes in the glucuronidation of apigenin, acacetin, and genkwanin in humans differ depending on the chemical structure of flavones.

Isoform-Specific Quantification of Human Bitter Taste Receptor Transcripts Using Real-Time PCR Analysis.

Bitter taste receptors (TAS2Rs) are expressed by oral cavity cells in mammals and classically function as sensors for bitter compounds. There are 25 functional isoforms of human TAS2Rs, with individual bitter ligands. Each human TAS2R isoform is distributed in several tissues, such as the airway epithelia and gastrointestinal tract, and plays an important role in physiological functions. However, quantification of each isoform is difficult because of highly homologous sequences between some TAS2R isoforms. Therefore, differentiating the isoforms by their expression levels is suitable for clarifying the tissue-specific effects of bitter compounds. In this study, we developed a real-time quantitative PCR (qPCR) method to determine the expression of each TAS2R isoform. Using plasmid standards harboring each isoform, we confirmed that the current assay can quantify the gene expression of each isoform, with negligible interference from other isoforms. In addition, our methods can successfully discriminate between the mRNA expression of each isoform in human cell lines and tissues. Therefore, this qPCR method can successfully quantify the mRNA level of each TAS2R isoform. This method will contribute to a better understanding of the molecular mechanisms underlying the TAS2R ligand-activated signal transduction.

In vitro glucuronidation of bisphenol A in liver and intestinal microsomes: interspecies differences in humans and laboratory animals.

Bisphenol A (BPA) is an endocrine-disrupting chemical, and is predominantly metabolized into glucuronide in mammals. The present study was conducted in order to examine the hepatic and intestinal glucuronidation of BPA in humans and laboratory animals such as monkeys, dogs, rats, and mice in an in vitro system using microsomal fractions. Km, Vmax, and CLint values in human liver microsomes were 7.54 µM, 17.7 nmol/min/mg protein, and 2.36 mL/min/mg protein, respectively. CLint values in liver microsomes of monkey, dogs, rats, and mice were 1.5-, 2.4-, 1.7- and 8.2-fold that of humans, respectively. In intestinal microsomes, Km, Vmax, and CLint values in humans were 39.3 µM, 0.65 nmol/min/mg protein, and 0.02 mL/min/mg protein, respectively. The relative levels of CLint in monkey, dogs, rats, and mice to that of humans were 7.0-, 12-, 34-, and 29-fold, respectively. Although CLint values were higher in liver microsomes than in intestinal microsomes in all species, and marked species difference in the ratio of liver to intestinal microsomes was observed as follows: humans, 118; monkeys, 25; dogs, 23; rats, 5.9; mice, 33. These results suggest that the functional roles of UDP-glucuronosyltransferase (UGT) enzymes expressed in the liver and intestines in the metabolism of BPA extensively differ among humans, monkeys, dogs, rats, and mice.

Favipiravir biotransformation in liver cytosol: Species and sex differences in humans, monkeys, rats, and mice.

Favipiravir is an antiviral agent effective against several RNA viruses that is converted into an inactive oxidative metabolite (M1), mainly by aldehyde oxidase, in humans. In the present study, the biotransformation of favipiravir into M1 in male and female humans, monkeys, rats, and mice was examined in an in vitro system using liver cytosolic fractions. The kinetics for M1 formation followed the Michaelis-Menten model in all species. The Km , Vmax , and CLint values in humans were 602 µM, 466 pmol/min/mg protein, and 776 nl/min/mg protein in males, respectively, and 713 µM, 404 pmol/min/mg protein, and 567 nl/min/mg protein in females, respectively. Species differences in CLint values were monkeys > humans > mice > rats in both males and females, and the variations for males and females were 120- and 96-fold, respectively. Sex differences in CLint values were males > females in humans and mice, females > males in monkeys and rats, and marked variation (4.3-fold) was noted in mice. This suggests that the roles of aldehyde oxidase in the hepatic metabolism of favipiravir differ extensively depending on the species and sex, and this study will aid in the assessment of the antiviral activities of favipiravir against novel and/or variant viruses.

Wogonin glucuronidation in liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice.

Wogonin, one of the flavonoids isolated from Scutellaria baicalensis, exhibits some beneficial bioactivities, including anti-inflammatory and anticancer effects, and is metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in humans. In the present study, wogonin glucuronidation was examined in the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice using a kinetic analysis.The kinetics of wogonin glucuronidation by liver microsomes followed the biphasic model in all species examined. CLint values (x-intercept) based on v versus V/[S] plots were rats > humans ≈ monkeys > mice > dogs. The kinetics of intestinal microsomes fit the Michaelis-Menten model for humans, monkeys, rats, and mice and the substrate inhibition model for dogs. CLint values were rats > monkeys > mice > dogs > humans. The tissue dependence of CLint values was liver microsomes > intestinal microsomes for humans, dogs, and rats, and liver microsomes ≈ intestinal microsomes for monkeys and mice.These results demonstrated that the metabolic abilities of UGT enzymes toward wogonin in the liver and intestines markedly differ among humans, monkeys, dogs, rats, and mice, and suggest that species differences are closely associated with the biological effects of wogonin.

S-equol glucuronidation in liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice.

S-equol, an active metabolite of the soy isoflavone daidzein, is mainly metabolized into glucuronide(s) by UDP-glucuronosyltransferase (UGT) enzymes in mammals. In the present study, S-equol glucuronidation was examined in the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice using a kinetic analysis. CLint values for 7- and 4'-glucuronidation by liver microsomes were higher than those by intestinal microsomes in all species. CLint values for total glucuronidation (sum of 7- and 4'-glucuronidation) were rats (7.6) > monkeys (5.8) > mice (4.9) > dogs (2.8) > humans (1.0) for liver microsomes, and rats (9.6) > mice (2.8) > dogs (1.3) ≥ monkeys (1.2) > humans (1.0) for intestinal microsomes, respectively. Regarding regioselective glucuronidation by liver and intestinal microsomes, CLint values were 7-glucuronidation > 4'-glucuronidation for humans, monkeys, dogs, and mice, and 4'-glucuronidation > 7-glucuronidation for rats. These results suggest that the metabolic abilities of UGT enzymes toward S-equol in the liver and intestines markedly differ among humans, monkeys, dogs, rats, and mice.

[A Case of Advanced Cardia Gastric Cancer with Pernicious Anemia].

A 70s male was referred to our hospital with anemia that was detected during a medical checkup. Upper gastrointestinal endoscopy showed advanced cardia gastric cancer. A diagnosis of pernicious anemia was made due to the macrocytic hyperchromic anemia and detection of intrinsic factor antibody. A CT scan showed fundic wall thickening and regional lymph node metastasis. After anemia improved following vitamin B12 injection, total gastrectomy with lymphadenectomy was performed. The histopathological findings showed adenocarcinoma(tub1>tub2), Type2 , pT3(SS), pN1(2/24), Stage ⅡB, INF b, ly1, v2, PM0, DM0, EW(+), pR1. He was administered systematic chemotherapy using S-1 for one year after surgery and has been followed up without recurrence for 5 years.

[A Case of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus Successfully Treated by Three-Dimensional Conformal Radiotherapy].

A man in his 50s was referred to our hospital with a liver tumor detected by ultrasonography during a medical checkup. Enhanced CT scan and MRI showed hepatocellular carcinoma(HCC)in S8 of the liver. Laparoscopic partial hepatectomy was performed. The histopathological findings showed well differentiated HCC. Two years later, his serum PIVKA-Ⅱ levels were slightly elevated. A new lesion was detected by US, CT, and MRI at S5 of the liver. A second laparoscopic partial hepatectomy was performed. The histopathological findings showed moderately differentiated HCC. After 1 year, MRI detected 2 new HCCs(S4, S8). The tumor at S8 had invaded the right branch of the portal vein. There was no indication for right hepatectomy because of liver dysfunction. Lipiodol-TACE followed by DEB-TACE was not effective on the tumor. The HCC at S8 had enlarged and formed a portal vein tumor thrombus. PIVKA- / Ⅱ levels increased to 3,596 mAU/mL. The patient was adminis- tered Three-dimensional conformal radiotherapy(45 Gy/15 Fr)and his PIVKA-Ⅱ levels decreased to the normal range. He has been followed-up without recurrences for 2 years and 9 months.

Hydrolysis of di(2-ethylhexyl) phthalate in humans, monkeys, dogs, rats, and mice: An in vitro analysis using liver and intestinal microsomes.

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that is rapidly metabolized to mono(2-ethylhexyl) phthalate (MEHP), an active metabolite, in mammals. In the present study, the hydrolysis of DEHP by the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice was examined. The kinetics of liver microsomes fit the Michaelis-Menten model for humans, monkeys, and rats, and the Hill model for dogs and mice. Km or S50 values were similar among species, whereas Vmax exhibited species differences of approximately 9-fold. CLint or CLmax values were in the order of mice > dogs > monkeys ≥ rats > humans. Hydrolytic activity towards DEHP was not detected in the intestinal microsomes of humans or dogs. The kinetics of monkeys, rats, and mice followed the Hill model. In comparisons of the liver microsomes of each species, S50 values were similar, while Vmax and CLmax values (mice > rats > monkeys) were considerably lower (approximately 5-25%). These results suggest that hydrolytic activity towards DEHP in the liver and intestines markedly differ among humans and non-rodent and rodent experimental animals, and imply that species differences are closely associated with the toxicity of DEHP.

Regioselective glucuronidation of daidzein in liver and intestinal microsomes of humans, monkeys, rats, and mice.

Daidzein, one of the major soy isoflavones, has a number of beneficial bioactivities for human health. It is mainly metabolized into 7- and/or 4'-glucuronides by UDP-glucuronosyltransferase (UGT) enzymes in mammals, including humans. The present study was conducted to examine the regioselective glucuronidation of daidzein at the 7- and 4'-hydroxyl groups in the liver and intestinal microsomes of humans, monkeys, rats, and mice. Daidzein glucuronidation activities at substrate concentrations of 1.0-200 µM were assessed, and Eadie-Hofstee plots were constructed. The kinetics for 7- and 4'-glucuronidation in the liver microsomes fit the Michaelis-Menten model, except for an atypical model for 7-glucuronidation in rats and a biphasic model for 4'-glucuronidation in monkeys. These kinetics in the intestinal microsomes followed the Michaelis-Menten model, except for a biphasic model for 7-glucuronidation in mice. The CLint values for 7-glucuronidation were in the order of monkeys (49) ≫ rats (5.3) > humans (1.0) > mice (0.7) for liver microsomes, and rats (2.4) ≥ monkeys (2.2) > humans (1.0) ≥ mice (0.8) for intestinal microsomes. On the other hand, the CLint values for 4'-glucuronidation were in the order of monkeys (4.0) > mice (1.0) ≈ humans (1.0) > rats (0.4) for liver microsomes, and humans (1.0) ≫ monkeys (0.08) ≥ mice (0.07) > rats (0.05) for intestinal microsomes. These results demonstrated that the metabolic abilities of UGT enzymes toward daidzein in the liver and intestines markedly differed among humans, monkeys, rats, and mice, and suggest that species and regioselective differences are closely associated with the bioactivities of soy isoflavones.

[Endoscopic Topical Therapy Using Mesh for Refractory Suture Failure after Rectal Cancer Surgery].

We reported a case that could be cured with endoscopic topical therapyusing mesh for refractorysuture failure after rectal cancer surgery. The patient was a 73-year-old man. He was diagnosed as lower rectal cancer, and underwent laparoscopic super law anterior rectum resection. On the 13th postoperative day, abdominal pain appeared, suspected ileal necrosis, emergencylaparoscopic examination laparotomywas performed. Upper gastrointestinal perforation was suspected from pus and food on the whole intraperitoneal cavity, and we moved laparotomy. But any perforations were not found, we resected ileum and inserted a drain tube to Douglas fossa. After second surgerydischarge of the juice from the drain was confirmed, diagnosis was made of suture failure of the anastomosis of the rectal cancer. He rejected artificial stomy, we chose conservative therapy. On 114th day after second surgerywe put a mesh for inguinal hernia in the puncture under the endoscope. On the next dayafter the treatment discharge of the juice from the drain was stopped. And finallyhe was discharged. This endoscopic treatment is considered to be useful for refractorysuture failure.

Naringenin glucuronidation in liver and intestine microsomes of humans, monkeys, rats, and mice.

Naringenin, a flavanone found in citrus fruits, is mainly metabolized into glucuronide(s) by UDP-glucuronosyltransferase (UGT) enzymes in mammals. In the present study, the glucuronidation of naringenin in the liver and intestine microsomes of humans, monkeys, rats, and mice was examined. The kinetics of 7-glucuronidation in human liver and intestine microsomes followed the Michaelis-Menten model. Kinetics in mouse liver and intestine microsomes also followed the Michaelis-Menten model, whereas those in monkey and rat liver microsomes fit the biphasic model. Kinetics in monkey and rat intestine microsomes fit the Michaelis-Menten and substrate inhibition models, respectively. CLint values were mice > monkeys > rats > humans for liver microsomes, and mice > rats > monkeys > humans for intestine microsomes. In 4´-glucuronidation, activities in human liver microsomes and monkey liver and intestine microsomes were negligible or very low. Kinetics in rat and mouse liver microsomes followed the biphasic and Michaelis-Menten models, respectively. CLint values were rats > mice for liver microsomes, and rats > mice > humans for intestine microsomes. These results suggest that the metabolic abilities and regioselectivity of UGT enzymes toward naringenin in the liver and intestines generally differ between primates and rodents.

Hepatic glucuronidation of 4-tert-octylphenol in humans: inter-individual variability and responsible UDP-glucuronosyltransferase isoforms.

4-tert-Octylphenol (4-tOP) is an endocrine-disrupting chemical. It is mainly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in humans. The purpose of this study was to assess inter-individual variability in and the possible roles of UGT isoforms in hepatic 4-tOP glucuronidation in the humans. 4-tOP glucuronidation activities in the liver microsomes and recombinant UGTs of humans were assessed at broad substrate concentrations, and kinetics were analyzed. Correlation analyses between 4-tOP and diclofenac or 4-hydroxybiphenyl activities in pooled and individual human liver microsomes were also performed. Typical CLint values were 17.8 mL/min/mg protein for the low type, 25.2 mL/min/mg protein for the medium type, and 47.7 mL/min/mg protein for the high type. Among the recombinant UGTs (13 isoforms) examined, UGT2B7 and UGT2B15 were the most active of catalyzing 4-tOP glucuronidation. Although the K m values of UGT2B7 and UGT2B15 were similar (0.36 and 0.42 µM, respectively), the CLint value of UGT2B7 (6.83 mL/min/mg protein) >UGT2B15 (2.35 mL/min/mg protein). Strong correlations were observed between the glucuronidation activities of 4-tOP and diclofenac (a probe for UGT2B7) or 4-hydroxybiphenyl (a probe for UGT2B15) with 0.79-0.88 of Spearman correlation coefficient (r s) values. These findings demonstrate that 4-tOP glucuronidation in humans is mainly catalyzed by hepatic UGT2B7 and UGT2B15, and suggest that these UGT isoforms play important and characteristic roles in the detoxification of 4-tOP.

Glucuronidation of 4-tert-octylphenol in humans, monkeys, rats, and mice: an in vitro analysis using liver and intestine microsomes.

4-tert-Octylphenol (4-tOP) is an endocrine-disrupting chemical. It is mainly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in mammals. In the present study, the glucuronidation of 4-tOP in humans, monkeys, rats, and mice was examined in an in vitro system using microsomal fractions. The kinetics of 4-tOP glucuronidation by liver microsomes followed the Michaelis-Menten model for humans and monkeys, and the biphasic model for rats and mice. The K m, V max, and CL int values of human liver microsomes were 0.343 µM, 11.6 nmol/min/mg protein, and 33.8 mL/min/mg protein, respectively. The kinetics of intestine microsomes followed the Michaelis-Menten model for humans, monkeys, and rats, and the biphasic model for mice. The K m, V max, and CL int values of human intestine microsomes were 0.743 µM, 0.571 nmol/min/mg protein, and 0.770 mL/min/mg protein, respectively. The CL int values estimated by Eadie-Hofstee plots were in the order of mice (high-affinity phase) (3.0) > humans (1.0) ≥ monkeys (0.9) > rats (high-affinity phase) (0.4) for liver microsomes, and monkeys (10) > mice (high-affinity phase) (5.6) > rats (1.4) > humans (1.0) for intestine microsomes. The percentages of the CL int values of intestine microsomes to liver microsomes were in the order of monkeys (27 %) > rats (high-affinity phase in liver microsomes) (7.9 %) > mice (high-affinity phase in liver and intestine microsomes) (4.2 %) > humans (2.3 %). These results suggest that the metabolic abilities of UGT enzymes expressed in the liver and intestine toward 4-tOP markedly differ among species and imply that species differences are strongly associated with the toxicities of alkylphenols.

[A Case of Long-Term Survival of Breast Cancer with Lymph Node and Liver Metastases Treated with Sequential Anti-HER2 Drugs, Chemotherapy, and Endocrine Therapy].

A 50s-year-old woman underwent left partial mastectomy with axillary lymphadenectomy for breast cancer. Histological examination indicated invasive ductal carcinoma, pT1c, pN0, Stage I , ly(+), ER(+), PgR(+). She received adjuvant therapy with tamoxifen and 50 Gy of irradiation to the residual breast. Four years after mastectomy, she was found to have left Rotter lymph node metastasis; then, anastrozole was administered instead of tamoxifen. Nine months later, she was found to have liver metastasis. Immunohistostaining revealed that the breast cancer was HER2-positive; she received AC followed by paclitaxel(PTX)with trastuzumab(T), and achieved complete response(CR). Subsequently, abdominal, cervical lymph node, and liver metastases appeared. Letrozole followed by lapatinib with capecitabine, FEC100, PTX with T, eribulin, S-1, docetaxel with pertuzumab and T, everolimus with exemestane, bevacizumab, and PTX were then administered, resulting in long-term disease control. Sixteen years after mastectomy, she receives outpatient chemotherapy in performance status 1 state.

[A Case of Squamous Cell Carcinoma of the Breast].

A 67-year-old woman presented with a 3 cm palpable mass in the lower lateral quadrant of her right breast. Mammography and ultrasonography showed a mass with an irregular border. Using fine needle aspiration biopsy and cytology, we detected malignant cells with keratosis, and made a diagnosis of squamous cell carcinoma(SCC). We performed total mastectomy with axillary lymph node dissection. Histologically, the tumor was identified as SCC with keratinization and a component of scirrhous adenocarcinoma; estrogen and progesterone receptor expression were not elevated. The tumor tested negative for HER2. The patient did not receive any adjuvant chemotherapy and is alive with no recurrence 13 years after surgery.