MDR1 Gene Polymorphism in Japanese Patients with Schizophrenia and Mood Disorders Including Depression

Abstract

Schizophrenia and depression has been reported to be associated with abnormal response of hypothalamus-pituitaryadrenal (HPA) system. [1][2][3][4][5] Dexamethasone suppression test (DST) has been used to assess the response of HPA system in several psychiatric disorders, [1][2][3][4][5][6] where suppression of plasma ACTH and cortisol via negative feedback was sometimes impaired. 6) Although the mechanisms for non-suppression of cortisol in DST has remained unclear, it has been suggested that pharmacokinetic alteration of dexamethasone was involved in non-suppressive patients with psychiatric disorders. 7,8) Penetration of dexamethasone into the brain is regulated by the blood-brain barrier (BBB) expressing P-gp (ABCB1-type P-gp), 9) multi-drug resistant (MDR1) gene encoding efflux pump, which protect the brain from several drugs. 10)Since P-gp is also known to be expressed on kidney, liver and intestine, 11) it is evident that phramacokinetic disposition of dexamethasone may be altered by P-gp activity. Muller et al. reported that mdr1 knockout mice enhanced dexamethasone sensitivity leading greater corticosterone suppression.12) This observation suggests that glucocorticoid response in DST is modified by P-gp expression on BBB, which is associated with MDR1 polymorphism. Higher expression of P-gp on BBB may produce poor access of dexamethasone to brain resulting in poor suppression of plasma cortisol levels, which is commonly observed in psychiatric disorders.Thus, P-gp as a neuroprotective barrier is likely to exert a influence on the pharmacodynamics of dexamethasone via BBB permeability, 12) as well as the etiology and pathogenesis of central nervous diseases such as Parkinson's disease. [13][14][15] We, therefore, investigated the single nucleotide polymorphisms (SNPs) on the MDR1 gene in patients with schizophrenia and mood disorders including depression, of which substantial population showed poor response to dexamethasone. SUBJECTS AND METHODSubjects were recruited in our hospital, Tsukuba university hospital in Japan. The diagnosis of schizophrenia (nϭ121) and mood disorders (nϭ62) was conducted according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV; American Psychiatric Association 1994). Subtype of each psychiatric disorder was indicated in Table 1. The control subjects (nϭ160) were patients receiving surgical operation (mastectomy, leg surgery and kidney transplantation), who had no present or past history of major psychiatric disorder including schizophrenia and mood disorders. Written informed consent was obtained from each participant. Blood samples were obtained from patients with schizophrenia, mood disorders and controls. The study was approved by the Ethical committee of University of Tsukuba. There was no different in age among the patients with schizophrenia and mood disorders, and the controls. P-Glycoprotein (ABCB1-type P-gp), a membrane protein encoded by the multi drug resistant gene (MDR1), expressing on the blood brain barrier protects the brain fro...

A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function

“…Current studies focus on the relationship of polymorphisms in the intronic region to diseases. It is suggested that some SNPs (-1517 T>C (promoter), -41 A>G (intron -1), -129 T>C (exon 1b)) may be associated with younger onset age of mood disorder [43]. Recently, a frequently occurring SNP in intron 13 (exon 13+81 C>T) has been found to be associated with sporadic colorectal cancer [44].…”

Implication of P-Glycoprotein in Formation of Depression-Prone Personality: Association Study between the C3435T <b><i>MDR1</i></b> Gene Polymorphism and Interpersonal Sensitivity

“…The MDR1 C3435T polymorphism is also associated with several neuropsychiatric disorders, i.e. Alzheimer's disease, Parkinson's disease, epilepsy and mood disorders [20,21,22]. This abundance of information on the association between P-glycoprotein function and disease susceptibility suggests the importance of this MDR1 gene polymorphism in genetic association studies.…”

Effects of ABCB1 3435C>T genotype on serum levels of cortisol and aldosterone in women with normal menstrual cycles

“…ABCB1 3435C>T genotype-dependent angiotensin II has been reported to increase serum aldosterone levels in male subjects (Zolk et al, 2007). Individuals with the ABCB1 haplotype, including 3435C>T polymorphism, are reportedly predisposed to mood disorders, presumably due to alteration of the plasma cortisol level, which is dependent on ABCB1 activity (Qian et al, 2006). However, it is not known whether ABCB1 genetic polymorphisms influence serum cortisol and aldosterone levels in female subjects and whether this influence varies across the menstrual cycle.…”