PharmGKB update: II. CYP3A5, cytochrome P450, family 3, subfamily A, polypeptide 5.
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Cytochrome P-450 CYP3A↗
Biomedical subjects
S Strom
Publications and source records attributed to S Strom.
Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450.
Sister of P-glycoprotein (SPGP) is the major hepatic bile salt export pump (BSEP). BSEP/SPGP expression varies dramatically among human livers. The potency and hierarchy of bile acids as ligands for the farnesyl/bile acid receptor (FXR/BAR) paralleled their ability to induce BSEP in human hepatocyte cultures. FXR:RXR heterodimers bound to IR1 elements and enhanced bile acid transcriptional activation of the mouse and human BSEP/SPGP promoters. In FXR/BAR nullizygous mice, which have dramatically reduced BSEP/SPGP levels, hepatic CYP3A11 and CYP2B10 were strongly but unexpectedly induced. Notably, the rank order of bile acids as CYP3A4 inducers and activators of pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR) closely paralleled each other but was markedly different from their hierarchy and potency as inducers of BSEP in human hepatocytes. Moreover, the hepatoprotective bile acid ursodeoxycholic acid, which reverses hydrophobic bile acid hepatotoxicity, activates PXR and efficaciously induces CYP3A4 (a bile-metabolizing enzyme) in primary human hepatocytes thus providing one mechanism for its hepatoprotection. Because serum and urinary bile acids increased in FXR/BAR -/- mice, we evaluated hepatic transporters for compensatory changes that might circumvent the profound decrease in BSEP/SPGP. We found weak MRP3 up-regulation. In contrast, MRP4 was substantially increased in the FXR/BAR nullizygous mice and was further elevated by cholic acid. Thus, enhanced hepatocellular concentrations of bile acids, due to the down-regulation of BSEP/SPGP-mediated efflux in FXR nullizygous mice, result in an alternate but apparent compensatory up-regulation of CYP3A, CYP2B, and some ABC transporters that is consistent with activation of PXR/SXR by bile acids.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.
Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.
Alleles↗
Promiscuous regulator of xenobiotic removal.
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ATP Binding Cassette Transporter, Subfamily B, Mem↗
The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants.
The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcriptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by endobiotics and xenobiotics. We cloned the human PXR gene and analysed the sequence in DNAs of individuals whose CYP3A phenotype was known. The PXR gene spans 35 kb, contains nine exons, and mapped to chromosome 13q11-13. Thirty-eight single nucleotide polymorphisms (SNPs) were identified including six SNPs in the coding region. Three of the coding SNPs are non-synonymous creating new PXR alleles [PXR*2, P27S (79C to T); PXR*3, G36R (106G to A); and PXR*4, R122Q (4321G to A)]. The frequency of PXR*2 was 0.20 in African Americans and was never found in Caucasians. Hepatic expression of CYP3A4 protein was not significantly different between African Americans homozygous for PXR*1 compared to those with one PXR*2 allele. PXR*4 was a rare variant found in only one Caucasian person. Homology modelling suggested that R122Q, (PXR*4) is a direct DNA contact site variation in the third alpha-helix in the DNA binding domain. Compared with PXR*1, and variants PXR*2 and PXR*3, only the variant PXR*4 protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays and attenuated ligand activation of the CYP3A4 reporter plasmids in transient transfection assays. However, the person heterozygous for PXR*4 is normal for CYP3A4 metabolism phenotype. The relevance of each of the 38 PXR SNPs identified in DNA of individuals whose CYP3A basal and rifampin-inducible CYP3A4 expression was determined in vivo and/or in vitro was demonstrated by univariate statistical analysis. Because ligand activation of PXR and upregulation of a system of drug detoxification genes are major determinants of drug interactions, it will now be useful to extend this work to determine the association of these common PXR SNPs to human variation in induction of other drug detoxification gene targets.
Alleles↗
Defining hepatocellular chimerism in a liver failure patient bridged with hepatocyte infusion.
BACKGROUND: A practical method of monitoring engraftment by transplanted hepatocytes for the purpose of bridging human liver failure to native regeneration is described. METHODS: A previously healthy 37-year-old female with a 2-week history of a febrile illness presented with fulminant liver failure. Findings on admission included the following: illicit drug use, serum hepatitis B surface antigen positive, grade 1 encephalopathy, prothrombin time (pt) >100 sec, F7<1%, NH3 150 micromol/L, alanine aminotransferase 4079 U/L, total bilirubin level 11.4 mg/dl, and glucose 70 mg/dl (on IV D10). With immunosuppression, 8.8x10(8), 96% viable human hepatocytes were intraportally infused. Clinical chemistries, total sHLA class I, and ELISA to measure donor-specific sHLA-A1 and -B8 were recorded. Serial transjugular liver biopsies were performed and pooled for histological examination, DNA extraction, and HLA DNA typing. RESULTS: The patient fully recovered. At months 3 and 4 with donor biopsy specimen class I HLA DNA no longer detectable, immunosuppression was tapered off. The patient is clinically normal, serum hepatitis B surface antigen negative at 10 months of follow-up. CONCLUSIONS: Bridging liver failure with donor hepatocytes with HLA class I antigen disparate from recipients is clinically feasible, and allows for a marker, combined with serial graft histology, to safely wean immunosuppression when native liver regeneration succeeds.
Adult↗
Obstetric outcomes in 102 pregnancies after preimplantation genetic diagnosis.
OBJECTIVE: We sought to determine whether preimplantation genetic diagnosis is associated with particular pregnancy or delivery complications. STUDY DESIGN: A total of 102 consecutive pregnancies after preimplantation genetic diagnosis by polar body removal performed at Illinois Masonic Medical Center resulting in 114 live births were analyzed. All patients were given a delivery and newborn questionnaire, and attempts were made to contact and question them regarding any pregnancy complications and type of delivery. Permission was obtained to examine medical records and discuss the patient's pregnancy with her obstetrician when questions existed with respect to complications or indication for cesarean delivery. RESULTS: Delivery and newborn questionnaires were completed or telephone contact was achieved for 100 of the 102 pregnancies. There were 85 singleton, 9 twin, and 7 triplet pregnancies. Of the 7 triplet gestations, 3 couples elected multifetal pregnancy reduction to twins and healthy triplets were born to 4 couples between 32 and 36 weeks by cesarean delivery. Of the 80 singleton deliveries, 60 (75%) progressed to term. Of these 60 term singleton deliveries, 34 were vaginal, 23 were cesarean (40%), and 3 delivery types were unknown. The incidence of small-for-gestational-age infants was 3% for neonates in the 60 term singleton deliveries and 7% in the entire cohort of 80 singleton deliveries. Only 3 pregnancy complications (other than premature delivery) were reported more than once. There were 3 instances each of gestational diabetes, intrauterine growth restriction, and pregnancy-induced hypertension. There was 1 case each of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, congestive heart failure, mild oligohydramnios, and abruptio placentae. The indications for cesarean delivery were (in descending order) failure of labor to progress (n = 7), fetal distress (n = 4), placenta previa (n = 4), elective repeat cesarean delivery (n = 4), triplets (n = 3), uterine scarring (n = 3), 1 twin in the breech position (n = 3), failed forceps delivery (n = 2), and a variety of other indications that occurred in only 1 patient each. All preimplantation genetic diagnoses were confirmed by prenatal or postnatal testing. No diagnostic errors were made in this cohort of patients or in any patients undergoing preimplantation genetic diagnosis having polar body removal in our center. CONCLUSIONS: Preimplantation genetic diagnosis is associated with a risk of multiple gestations, cesarean delivery, and placenta previa. Cesarean delivery rates and multiple gestation rates are comparable to those of patients undergoing in vitro fertilization in general. The preimplantation genetic diagnosis itself does not seem to cause an increased risk for any particular pregnancy complication, with the possible exception of placenta previa, which was seen in 4% of patients.
Cesarean Section↗
Neonatal outcome of preimplantation genetic diagnosis by polar body removal: the first 109 infants.
CONTEXT: Our center developed the technique of preimplantation genetic diagnosis (PGD) by sequential polar body removal (PBR) for the diagnosis of Mendelian disorders and aneuploidies. This study examines the obstetric and neonatal outcome of the first 109 live births after PGD by PBR. OBJECTIVE: To determine if there were any observable effects of PGD by PBR on perinatal morbidity and mortality, birth defects, and growth parameters. DESIGN: Data on perinatal outcome were gathered for the first 109 infants by parental reporting and confirmed by telephone interview and chart review when indicated. In infants >6 months old, a follow-up telephone interview was performed establishing the developmental milestones attained by the child. SETTING: A research center conducting an institutional review board-approved research protocol in PGD. PATIENTS: All patients who had PGD by PBR who had clinical pregnancies. MAIN OUTCOME MEASURES: Gestational age, mode of delivery, perinatal mortality, birth weight, birth length, the presence of birth defects, and developmental milestones. RESULTS: There was no significant decrease in birth length or weight, or the frequency of small for gestational age infants. No specific pattern of birth defects was observed. CONCLUSION: Thus far, there are no observable detrimental effects of PGD by PBR on children born after the procedure.
Aneuploidy↗
Current status of intestinal transplantation in children.
PURPOSE: A clinical trial of intestinal transplantation (Itx) under tacrolimus and prednisone immunosuppression was initiated in June 1990 in children with irreversible intestinal failure and who were dependent on total parenteral nutrition (TPN). METHODS: Fifty-five patients (28 girls, 27 boys) with a median age of 3.2 years (range, 0.5 to 18 years) received 58 intestinal transplants that included isolated small bowel (SB) (n = 17), liver SB (LSB) (n=33), and multivisceral (MV) (n=8) allografts. Nine patients also received bone marrow infusion, and there were 20 colonic allografts. Azathioprine, cyclophosphamide, or mycophenolate mofetil were used in different phases of the series. Indications for Itx included: gastroschisis (n=14), volvulus (n=13), necrotizing enterocolitis (n=6), intestinal atresia (n=8), chronic intestinal pseudoobstruction (n=5), Hirschsprung's disease (n=4), microvillus inclusion disease (n=3), multiple polyposis (n=1), and trauma [n=1). RESULTS: Currently, 30 patients are alive (patient survival, 55%; graft survival, 52%). Twenty-nine children with functioning grafts are living at home and off TPN, with a mean follow-up of 962 (range, 75 to 2,424) days. Immunologic complications have included liver allograft rejection (n=18), intestinal allograft rejection (n=52), posttransplant lymphoproliferative disease (n=16), cytomegalovirus (n=16) and graft-versus-host disease (n=4). A combination of associated complications included intestinal perforation (n=4), biliary leak (n=3), bile duct stenosis (n=1), intestinal leak (n=6), dehiscence with evisceration (n=4), hepatic artery thrombosis (n=3), bleeding (n=9), portal vein stenosis (n=1), intraabdominal abscess (n=11), and chylous ascites (n=4). Graft loss occurred as a result of rejection (n=8), infection (n=12), technical complications (n=8), and complications of TPN after graft removal (n=3). There were four retransplants (SB, n=1; LSB n=3). CONCLUSIONS: Intestinal transplantation is a valid therapeutic option for patients with intestinal failure suffering complications of TPN. The complex clinical and immunologic course of these patients is reflected in a higher complication rate as well as patient and graft loss than seen after heart, liver, and kidney transplantation, although better than after lung transplantation.
Child, Preschool↗
Long-term follow-up of patients with newly diagnosed acute myeloid leukemia treated at the University of Texas M.D. Anderson Cancer Center.
BACKGROUND: Chemotherapy is known to cure a small minority of patients with acute myeloid leukemia (AML). Less is known about the risk of such patients developing subsequent cancers or about their ability to return to work. METHODS: The authors analyzed outcomes among 1892 patients who received treatment for newly diagnosed AML at the University of Texas M. D. Anderson Cancer Center from 1965 to May 1995. RESULTS: Because failure rates declined to relatively low levels after a first or later complete remission of > or = 3 years' duration, such patients comprised a "potentially cured" cohort. The criterion for entry into this cohort was fulfilled by 215 patients (10.7%; 203 in first complete remission and 12 in second remission). At a median of 6.2 years after entry into the cohort (i.e., 9.2 years from complete remission), 163 patients (76%) remain alive and in complete remission. Approximately 9% and 5% of the 1892 patients have been in complete remission for > 5 years and > 10 years, respectively. The pretreatment prognostic importance of cytogenetics is still apparent even after 5 years in complete remission. On average, members of the potentially cured cohort were not observed to be at increased risk of subsequent invasive malignancies compared with a normal population. Furthermore, two-thirds of those in the potentially cured cohort who were working full time before diagnosis of AML claimed to have returned to full-time work. Of those not working, only 10% cited physical limitation as the reason. CONCLUSIONS: The major threat to the life and well-being of the patient with AML is clearly the disease and not its treatment.
Acute Disease↗
Building a theory of grandparent development.
A theory of grandparent development is described that includes the formulation of assumptions, goals for guiding instruction, curriculum design, and a measurement tool to assess learning needs and evaluate the effects of educational intervention. Cultural considerations are illustrated by a three generational study of African-American (n = 777), Caucasian (n = 1086), and Hispanic (n = 672) subjects who were administered the Grandparent Strengths and Needs Inventory. Perceptions of each generation about the attitudes and behaviors of grandparents were examined with multivariate analysis of variance and post-hoc comparisons to analyze the scores, confirm results, and facilitate interpretation of findings. Results showed significant differences between generations and within cultures. Each generation identified elements of grandparent success as well as issues that deserve consideration in building educational programs.
Attitude↗
Grandparents in Taiwan: a three-generational study.
Grandparents in the Republic of China want to remain influential, but social policy has not provided them with education to fulfill their changing role. The performance of grandparents was examined to determine suitable content for an intervention program. A sample of 751 non-consanguineous participants from urban and rural Taiwan included 234 grandparents, 241 parents, and 276 grandchildren. Each generation was administered a separate version of the Grandparent Strengths and Needs Inventory that was translated into Mandarin. Respondents identified favorable qualities of grandparents as well as aspects of their relationships in which growth was necessary. Multivariate analysis of variance, univariate analysis of variance, Scheffé and t-tests were used to analyze scores, confirm results, and facilitate interpretation. All three generations described aspects of grandparent success and specific realms of learning they should acquire to become more effective. Significant main effects that influenced responses about grandparent performance were generation, gender of grandchild, age of grandchild, frequency of grandchild care by grandparent, generations living together, and amount of time grandparent and grandchild spent together. Considerations were recommended to improve behavior of grandparents and guide the development of educational programs for them.
Aged↗
Black grandparents: curriculum development.
The performance of Black grandparents was examined to determine the most suitable content for an educational program intended to assist them in their role. A sample of 626 non-consanguineous subjects included 204 grandparents, 128 parents, and 294 grandchildren. Each generation group completed a separate version of the Grandparent Strengths and Needs Inventory to identify the favorable qualities of grandparents and aspects of their relationships in which further growth was necessary. A combination of multivariate analysis of variance procedures, univariate analysis of variance tests, and t-tests were used to analyze scores, confirm results, and assist with interpretation of data. All groups described aspects of grandparents success and made known specific realms of learning that grandparents should acquire in order to become more effective. Analysis of the responses revealed significant main effects for generation, gender of grandchild, age of grandchild, and amount of time that grandparent and grandchild spent together. Considerations were identified for improving grandparent influence and guiding the development of grandparent education programs.
Adolescent↗
Identification of a novel dexamethasone responsive enhancer in the human CYP3A5 gene and its activation in human and rat liver cells.
The human liver cytochromes P450 3A (CYP3As), orthologous to the rat glucocorticoid inducible forms, are composed of at least four differentially expressed members. To begin the study of the molecular events in the glucocorticoid regulation of CYP3A5, we fused 5' sequences of CYP3A5 to the chloramphenicol acetyltransferase gene in a vector that contains the herpes simplex virus thymidine kinase promoter. In HepG2 cells, the largest 5' CYP3A5 gene fragment (1.4 kb) suppressed the TK promoter. However, suppression was overcome by addition of 10 microM dexamethasone. A series of unidirectional deletions revealed a unique 219-bp fragment (-891 to -1109 bp upstream from the transcriptional start site) that conferred dexamethasone responsiveness on the TK promoter regardless of either the distance or orientation from the promoter and thus appears to be an enhancer. Nucleotide sequence analysis of this CYP3A5 enhancer revealed no consensus 15-bp glucocorticoid responsive element (GRE) (GGTACANNNTGTTCT); however, two GRE "half-sites" (TGTTCT) were found separated by 160 bp. Although dexamethasone stimulated the CYP3A5 enhancer only 3-4-fold in HepG2 cells, the CYP3A5 enhancer was stimulated 7- and 12-fold in immortalized primary human hepatocytes and primary rat hepatocyte cultures, respectively. The glucocorticoid receptor (GCR) seems to be indispensable to this process because 1) dexamethasone induction can be blocked by the antiglucocorticoid RU-486, 2) dexamethasone-dependent transcriptional activation of the CYP3A5 enhancer in HepG2 cells required cotransfection of an expression vector containing the intact GCR, yet 3) cotransfection with a plasmid that contains a mutation in the ligand binding domain of the GCR does not activate the CYP3A5 enhancer in the presence of dexamethasone. To further localize the dexamethasone responsive region of the 219-bp CYP3A5 enhancer, it was subdivided and fused to the TKCAT expression vector. Transfection analysis in HepG2 cells demonstrated that neither GRE half-site can independently confer dexamethasone responsiveness on the TK promoter. Block mutations of either of the two GRE half-sites or point mutations at specific GCR binding sites eliminates dexamethasone inducibility, demonstrating the half-sites need to interact. Electromobility shift assays indicate that the CYP3A5 5'-GRE half-site 1) specifically binds purified GCR, 2) can displace binding of the GCR to a consensus GRE, and 3) shifts a protein in HepG2 nuclear extracts that is supershifted by GCR antibody, demonstrating that this enhancer is an authentic GRE. This is the first study to demonstrate that a member of the human CYP3A gene family contains an enhancer that binds the GCR and that this binding is critical to transcriptional activation by dexamethasone.
Animals↗
Grandparents in Japan: a three-generational study.
Grandparents in Japan believe that their status in the family is eroding. They want to be influential but social policy has not included education for their changing role. The purpose of this study was to identify strengths and needs of Japanese grandparents as perceived by three generations. Each generation completed a separate version of the Grandparent Strengths and Needs Inventory. Multivariate analysis of variance procedures were used to compare perceptions of 239 grandparents, 266 parents, and 274 school-age grandchildren from cities and small towns. Grandparents reported more satisfaction, greater success, and more extensive involvement in teaching than was observed by parents and grandchildren. Grandparents experienced greater difficulty, more frustration, and felt less informed to carry out their role than was reported by parents and grandchildren. Significant main effects that influenced responses about grandparent performance were generation, gender of grandchild, age of grandchild, generations living together, frequency of grandchild care by grandparent, and amount of time they spent together. Considerations were identified to improve grandparent behavior and guide the development of educational programs for them.
Aged↗
Short exposure to hepatocyte growth factor stimulates adult human pancreatic beta-cell proliferation.
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Adult↗
Localization of epidermal growth factor receptor by immunohistochemical methods in human prostatic carcinoma, prostatic intraepithelial neoplasia, and benign hyperplasia.
The epidermal growth factor receptor (EGFr) is a membrane-bound glycoprotein that is present in a wide variety of human normal and malignant tissues. In this study EGFr expression in frozen sections of prostate tissue obtained from 40 different surgical specimens was examined immunohistochemically with a well-characterized monoclonal antibody to EGFr, Ab-1 (Oncogene Science). Twenty cases of prostate adenocarcinoma and 20 cases of benign prostatic hyperplasia were studied. Six of the 20 cases of adenocarcinoma also contained prostatic intraepithelial neoplasia grade III (severe intraductal dysplasia). All of the cases containing benign glands showed strong immunostaining in a continuous or nearly continuous pattern, with staining restricted to the basal layer of the benign glands. Adenocarcinoma lacked immunostaining in 15 (75%) of 20 cases, while the remaining five cases (25%) showed diffuse cytoplasmic staining, which was weaker than that seen in the benign glands and that lacked basal accentuation. The six cases that contained prostatic intraepithelial neoplasia grade III showed a discontinuous basal pattern of staining, and the gaps in the staining appeared to correspond to areas of disruption of the basal cell layer. We conclude that the antigenic determinant recognized by this antibody to EGFr was detected preferentially in the basal layer in benign prostatic glands. In contrast, a minority of cases of adenocarcinoma expressed EGFr, as assessed by immunoreactivity with the Ab-1 monoclonal antibody. Prostatic intraepithelial neoplasia grade III expressed EGFr with a predominantly discontinuous basal pattern that corresponded to the disrupted basal cell layer typical of this process.
Adenocarcinoma↗
Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients.
This paper presents the analysis of familial cancer data collected in a hospital-based study of 159 childhood soft-tissue-sarcoma patients. Two different statistical models detected excess aggregation of cancer, which could be explained by a rare dominant gene. For each kindred, we estimated the probability of the observed cancer distribution under the dominant-gene model and identified 12 families that are the most likely to be segregating the gene. Two of those families have confirmed germ-line mutations in the p53 tumor-suppressor gene. The relative risk of affection for children who are gene carriers was estimated to be 100 times the background rate. Females were found to have a slightly higher age-specific penetrance, but maternal and paternal lineages made equal contributions to the evidence in favor of the dominant gene. The proband's histology, ethnicity, and age at diagnosis were evaluated to determine whether any of these altered the probability of affection in family members. Only embryonal rhabdomyosarcoma was found to be a significant covariate under the dominant-gene model. While molecular genetic studies of familial cancer will eventually provide answers to the questions of genetic heterogeneity, age- and site-specific penetrance, mutation rates, and gene frequency, information from statistical models is useful for setting priorities and defining hypotheses.
Adolescent↗