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Neurogenic Lower Urinary Tract and Sexual Dysfunction
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Karl H. Pang, Nadir I. Osman, Altaf Mangera
Cause: failure of neural tube closure.Folate deficiencyMutation of 5,10-Methylenetetrahydrofolate reductase gene
Pharmacology, Pharmacogenetics, and Pharmacoepidemiology: Three P’s of Individualized Therapy
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Methyltetrahydrofolate reductase (MTHFR), a crucial enzyme in the metabolism of folic acid, catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (the predominant circulatory form of folate and the carbon donor for the demethylation of homocysteine to methionine). As methotrexate increases serum levels of homocysteine and the active polyglutamate metabolites of methotrexate inhibit MTHFR function, patients with a low level of MTHFR function are at an increased risk of methotrexate-induced toxicities such as oral mucosities. Two polymorphisms associated with reduced MTHFR activity have been described (25): (i) 677C > T polymorphism that is homozygous in 10% of the population where it encodes the enzyme with 30% of the wild-type enzyme activity and heterozygous in 40% of the population where it encodes an enzyme that has 60% of the wild type-enzyme activity and (ii) 1298A > C (less common than 677C > T). Recent findings have also suggested that MTHFR polymorphisms may protect against the development of both adult and pediatric ALL (26).
Hereditary and Acquired Causes of a Hypercoagulable State
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Recently, several molecular assays have been reported which identify the more common genetic mutations in enzymes of the homocysteine pathway. The most common cause of an inherited predisposition to mild hyperhomocysteinemia is believed to be the presence of a polymorphism in the gene for the enzyme 5, 10-methylenetetrahydrofolate reductase, MTHFR (C677T) (34). This translates to an alanine-to-valine amino acid substitution and results in a thermolabile form of the enzyme with 38% enzyme activity in the homozygous form and 65% in the heterozygous form versus 100% in the wild type (35). The homozygous and heterozygous forms of this mutation occur in the 10–12% and 40–45% of the North American Caucasian population, respectively. A mutation, T833C, in the CBS gene, is found in as high as 1.4% of the general population, and an association with thromboembolic disease has been suggested (30).
Association Between Vitamin B6 and the Risk of Colorectal Cancer: A Meta-analysis of Observational Studies
Published in Nutrition and Cancer, 2023
Jianxiong Lai, Mingqiao Guo, Dongmei Wang, Kuan Liu, Dengmin Hu, Jian Li
Vitamin B6 is an important component of the B vitamins and is widely found in cereals, meat, fish, poultry, vegetables, and some fruits. Dietary vitamin B6 is absorbed in the intestine and metabolized in the liver to pyridoxal 5′-phosphate (PLP) and subsequently enters the blood, where it serves as a coenzyme for more than 160 different reactions in multiple metabolic pathways (6). For example, vitamin B6 acts as a coenzyme of serine hydroxymethyl transferase in the synthesis of 5,10-methylenetetrahydrofolate (7, 8). Furthermore, vitamin B6 is also a coenzyme of cystathionine β-synthase and cystathionine γ-lyase; the former condenses homocysteine and serine into cystathionine, and the latter converts cystathionine into cysteine (9). As vitamin B6 participates in various metabolic reactions as a coenzyme, it is thought to reduce the susceptibility to colorectal cancer (10).
Systematic review and meta-analysis of the predictive power of MTHFR polymorphisms for pemetrexed drug efficacy and toxicity in non-small cell lung cancer patients
Published in Journal of Chemotherapy, 2022
Currently, cytotoxic chemotherapy and radiotherapy are essential components of the systemic treatment of lung cancer. Pemetrexed (PEM) is commonly used to treat patients with adenocarcinoma-type NSCLC in combination with platinum compounds to extend patient life [6,7]. ,PEM is a multi-target folate antagonist that inhibits at least three enzymes during folate metabolism as well as purine and pyrimidine synthesis, the most essential of which is thymidylate synthase (TS) [8]. TS is folate-dependent enzyme involved in DNA synthesis, DNA repair, and proliferation of cancer cells. The primary metabolite of folate is 5,10-methylenetetrahydrofolate (5,10-MTHF), which is mainly absorbed by the intestinal cells and converted to 5-MTHF by 5,10-methylene tetrahydrofolate reductase (MTHFR) [9,10]. The MTHFR enzyme plays an important role in the regulation of the ratio of 5,10-MTHF and 5-MTHF. Abnormal folate metabolism leads to defects in DNA synthesis or S-adenosyl methionine (SAM) synthesis, which affects the normal cell cycle and can lead to cell death [11,12]. A study conducted in 2017 reported that the concentration of 5-MTHF tended to be higher in PEM responders compared to in non-responders (P = 0.06) [13]. Therefore, folate levels may be predictive of the response to PEM treatment.
High dose methotrexate in adult Egyptian patients with hematological malignancies: impact of ABCB1 3435C > T rs1045642 and MTHFR 677C > T rs1801133 polymorphisms on toxicities and delayed elimination
Published in Journal of Chemotherapy, 2022
Abdel-Hameed I. M. Ebid, Ahmed Hossam, Mosaad M. El Gammal, Sameh Soror, Nadia O.M Mangoud, Mohamed Adel Mahmoud
Pharmacogenetic-based studies have been extensively conducted to study and provide a plausible method of predicting these multiple toxicity outcomes. These studies searched for a significant role of various related single nucleotide polymorphisms (SNPs) in genes encoding key regulators in the essential pathways of MTX in our body with variable and conflicting conclusions [11,12]. Amongst these essential regulators, the methylenetetrahydrofolate reductase (MTHFR), which is an essential enzyme in the folic acid cycle as it induces the conversion of 5, 10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which is the active and predominant form of folate in the circulation. The most common studied polymorphism in that regulator gene is ‘677 C > T’ rs1801133 which reduces the activity of the enzyme [3,11,13–15]. Among other important key regulators are a group of transporters called ATP binding cassette (ABC), which include subfamily B member 1 (ABCB1), and it is known as p-glycoprotein-1; they play an important role in exporting MTX outside the cell; hence it may affect MTX clearance. One of the most commonly studied gene polymorphisms in these transporters is ABCB1 3435 C > T rs1045642; it is associated with reduced activity of that transporter and may cause MTX delayed elimination and increased risk of toxicity [3,16–19].