Bioactivation, Mutagenicity, DNA Damage, and Oxidative Stress Induced by 3,4-Dimethylaniline.

3,4-Dimethylaniline (3,4-DMA) is present in cigarette smoke and widely used as an intermediate in dyes, drugs, and pesticides. Nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells stably transfected with human CYP1A2 and N-acetyltransferase 1 (NAT1) alleles: (reference allele) or (the most common variant allele) were utilized to assess 3,4-DMA -acetylation and hypoxanthine phosphoribosyl transferase (HPRT) mutations, double-strand DNA breaks and reactive oxygen species (ROS). CHO cells expressing exhibited significantly ( < 0.

Remote organ cancer induces kidney injury, inflammation, and fibrosis and adversely alters renal function.

Approximately 30% of the patients with cancer experience kidney complications, which hinder optimal cancer management, imposing a burden on patients' quality of life and the healthcare system. The etiology of kidney complications in patients with cancer is often attributed to oncological therapies. However, the direct impact of cancer on kidney health is underestimated.

Expression of Ceramide Synthases in Mice and Their Roles in Regulating Acyl-Chain Sphingolipids: A Framework for Baseline Levels and Future Implications in Aging and Disease.

Sphingolipids are an important class of lipids present in all eukaryotic cells that regulate critical cellular processes. Disturbances in sphingolipid homeostasis have been linked to several diseases in humans. Ceramides are central in sphingolipid metabolism and are largely synthesized by six ceramide synthase (CerS) isoforms (CerS1-6), each with a preference for different fatty acyl chain lengths.

The effect of the rs1799931 G857A (G286E) polymorphism on N-acetyltransferase 2-mediated carcinogen metabolism and genotoxicity differs with heterocyclic amine exposure.

Human N-acetyltransferase 2 (NAT2) is subject to genetic polymorphism in human populations. In addition to the reference NAT2*4 allele, two genetic variant alleles (NAT2*5B and NAT2*7B) are common in Europe and Asia, respectively. NAT2*5B possesses a signature rs1801280 T341C (I114T) single-nucleotide polymorphism (SNP), whereas NAT2*7B possesses a signature rs1799931 G857A (G286E) SNP.

Effect of N-acetyltransferase 2 genetic polymorphism on 4,4'-methylenebis(2-chloroaniline)-induced genotoxicity and oxidative stress.

4,4'-Methylenebis(2-chloroaniline) or MOCA is an aromatic amine used primarily in polyurethane and rubber industry. MOCA has been linked to hepatomas in animal studies while limited epidemiologic studies reported the association of exposure to MOCA and urinary bladder and breast cancer. We investigated MOCA-induced genotoxicity and oxidative stress in DNA repair-deficient Chinese hamster ovary (CHO) cells stably transfected with human metabolizing enzymes CYP1A2 and N-acetyltransferase 2 (NAT2) variants as well as in rapid, intermediate, and slow NAT2 acetylator cryopreserved human hepatocytes.

Association between cigarette smoking and ovarian reserve among women seeking fertility care.

Introduction: This study examined the association of smoking with ovarian reserve in a cross-sectional study of 207 women enrolled in the Louisville Tobacco Smoke Exposure, Genetic Susceptibility, and Infertility (LOUSSI) Study and assessed effect modification by NAT2 acetylator phenotype.

Methods: Information on current smoking status was collected using a structured questionnaire and confirmed by cotinine assay. Serum anti-Müllerian hormone (AMH) levels were used to assess ovarian reserve.

Dataset for proteomic analysis of arylamine -acetyltransferase 1 knockout MDA-MB-231 breast cancer cells.

Arylamine -acetyltransferase 1 () is frequently upregulated in breast cancer. An unbiased analysis of proteomes of parental MDA-MB-231 breast cancer cells and two separate knockout (KO) cell lines were performed. Among 4,890 proteins identified, 737 and 651 proteins were found significantly ( < 0.

Acetyl coenzyme A kinetic studies on -acetylation of environmental carcinogens by human -acetyltransferase 1 and its variant.

N-acetyltransferase 1 (NAT1) is a xenobiotic metabolizing enzyme that uses acetyl coenzyme A (AcCoA) as a cofactor for -acetylation of many carcinogens including aromatic amines and alkylanilines. NAT1 is characterized by single nucleotide polymorphisms (SNPs) that may modulate affinity towards AcCoA. In the current study, we used Chinese hamster ovary (CHO) cells stably transfected with human (reference allele) or (variant allele) to measure AcCoA kinetic parameters for -acetyltransferase activity measurements towards -aminobenzoic acid (PABA), 4-aminobiphenyl (4-ABP), β-naphthylamine (BNA), benzidine and 3,4-dimethylaniline (3,4-DMA).

Upregulation of cytidine deaminase in NAT1 knockout breast cancer cells.

Purpose: Arylamine N-acetyltransferase 1 (NAT1), a phase II metabolic enzyme, is frequently upregulated in breast cancer. Inhibition or depletion of NAT1 leads to growth retardation in breast cancer cells in vitro and in vivo. A previous metabolomics study of MDA-MB-231 breast cancer cells suggests that NAT1 deletion leads to a defect in de novo pyrimidine biosynthesis.

Proteomic analysis of arylamine -acetyltransferase 1 knockout breast cancer cells: Implications in immune evasion and mitochondrial biogenesis.

Previous studies have shown that inhibition or depletion of -acetyltransferase 1 (NAT1) in breast cancer cell lines leads to growth retardation both in vitro and in vivo, suggesting that NAT1 contributes to rapid growth of breast cancer cells. To understand molecular and cellular processes that NAT1 contributes to and generate novel hypotheses in regard to NAT1's role in breast cancer, we performed an unbiased analysis of proteomes of parental MDA-MB-231 breast cancer cells and two separate knockout (KO) cell lines. Among 4890 proteins identified, 737 proteins were found significantly ( < 0.

N-acetyltransferase 2 genetic polymorphism modifies genotoxic and oxidative damage from new psychoactive substances.

The use of new psychoactive substances (NPS) as drugs of abuse is common and increasingly popular, particularly among youth and neglected communities. Recent studies have reported acute toxic effects from these chemicals; however, their long-term toxicity is unknown. Genetic differences between individuals likely affect the toxicity risk.

F4/80 Resident Macrophages Contribute to Cisplatin-Induced Renal Fibrosis.

Background: Cisplatin-induced kidney injury remains a major obstacle in utilizing cisplatin as a chemotherapeutic for solid-organ cancers. Thirty percent of patients treated with cisplatin develop acute kidney injury (AKI), and even patients who do not develop AKI are at risk for long-term declines in kidney function and development of chronic kidney disease (CKD). Modeling cisplatin-induced kidney injury in mice has revealed that repeated low doses of cisplatin lead to development of kidney fibrosis.

N-acetyltransferase 2 acetylator genotype-dependent N-acetylation and toxicity of the arylamine carcinogen β-naphthylamine in cryopreserved human hepatocytes.

We used cryopreserved human hepatocytes that express rapid, intermediate, and slow acetylator N-acetyltransferase 2 (NAT2) genotypes to measure the N-acetylation of β-naphthylamine (BNA) which is one of the aromatic amines found in cigarette smoke including E-cigarettes. We investigated the role of NAT2 genetic polymorphism in genotoxicity and oxidative stress induced by BNA. In vitro BNA NAT2 activities in rapid acetylators was 1.

Differences in β-naphthylamine metabolism and toxicity in Chinese hamster ovary cell lines transfected with human CYP1A2 and NAT2*4, NAT2*5B or NAT2*7B N-acetyltransferase 2 haplotypes.

β-naphthylamine (BNA) is an important aromatic amine carcinogen. Current exposures derive primarily from cigarette smoking including e-cigarettes. Occupational and environmental exposure to BNA is associated with urinary bladder cancer which is the fourth most frequent cancer in the United States.

Pharmacological inhibitors of autophagy have opposite effects in acute and chronic cisplatin-induced kidney injury.

The nephrotoxicity of cisplatin remains a major hurdle in the field of oncology. Thirty percent of patients treated with cisplatin develop acute kidney injury, and all patients are at risk for long-term impacts on kidney function. There are currently no Federal Drug Administration-approved agents to prevent or treat cisplatin-induced kidney injury.

Hexavalent chromium increases the metabolism and genotoxicity of aromatic amine carcinogens 4-aminobiphenyl and β-naphthylamine in immortalized human lung epithelial cells.

Humans are exposed to carcinogenic chemicals via occupational and environmental exposures. Common chemicals of concern that can occur in exposures together are aromatic amines (e.g.

Neutral ceramidase-dependent regulation of macrophage metabolism directs intestinal immune homeostasis and controls enteric infection.

It is not clear how the complex interactions between diet and intestinal immune cells protect the gut from infection. Neutral ceramidase (NcDase) plays a critical role in digesting dietary sphingolipids. We find that NcDase is an essential factor that controls intestinal immune cell dynamics.

Human -Acetyltransferase 1 and 2 Differ in Affinity Towards Acetyl-Coenzyme A Cofactor and -Hydroxy-Arylamine Carcinogens.

Arylamine N-acetyltransferases catalyze the transfer of acetyl groups from the endogenous cofactor acetyl coenzyme A (AcCoA) to arylamine (-acetylation) and -hydroxy-arylamine (-acetylation) acceptors. Humans express two arylamine -acetyltransferase isozymes (NAT1 and NAT2) which catalyze both - and -acetylation but differ in genetic regulation, substrate selectivity, and expression in human tissues. We investigated recombinant human and expressed in an JM105 and expression systems as well as in Chinese hamster ovary (CHO) cells to assess the relative affinity of AcCoA for human NAT1 and NAT2.

560G>A (rs4986782) (R187Q) Single Nucleotide Polymorphism in Arylamine N-Acetyltransferase 1 Increases Affinity for the Aromatic Amine Carcinogens 4-Aminobiphenyl and N-Hydroxy-4-Aminobiphenyl: Implications for Cancer Risk Assessment.

Human arylamine N-acetyltransferase 1 (NAT1) catalyzes the N-acetylation of arylamine carcinogens such as 4-aminobiphenyl (ABP), and following N-hydroxylation, the O-acetylation of N-hydroxy-arylamine carcinogens such as N-hydroxy-ABP (N-OH-ABP). Genetic polymorphisms in NAT1 are linked to cancer susceptibility following exposures. The effects of individual single nucleotide polymorphisms (SNPs) in the NAT1 coding exon on Michaelis-Menten kinetic constants was assessed for ABP N-acetyltransferase and N-OH-ABP O-acetyltransferase activity following transfection of human NAT1 into COS-1 cells (SV40-transformed African green monkey kidney cells).

Arylamine -Acetyltransferase 1 Activity is Regulated by the Protein Acetylation Status.

Arylamine -acetyltransferase 1 (NAT1) is a drug metabolizing enzyme that influences cancer cell proliferation and survival, especially in breast cancer. Lysine-acetylation is an important Post-Translational Modification (PTM) in the regulation of diverse cellular processes. Histone deacetylases (HDACs) and Sirtuins (SIRT) may have an important role on the NAT1 acetylation status, affecting its catalytic capacity and having an impact on the downstream functions of this protein.

Neutral ceramidase deficiency protects against cisplatin-induced acute kidney injury.

Cisplatin is a commonly used chemotherapeutic for the treatment of many solid organ cancers; however, its effectiveness is limited by the development of acute kidney injury (AKI) in 30% of patients. AKI is driven by proximal tubule cell death, leading to rapid decline in renal function. It has previously been shown that sphingolipid metabolism plays a role in regulating many of the biological processes involved in cisplatin-induced AKI.

Deletion of arylamine N-acetyltransferase 1 in MDA-MB-231 human breast cancer cells reduces primary and secondary tumor growth in vivo with no significant effects on metastasis.

Arylamine N-acetyltransferase 1 (NAT1) is frequently upregulated in breast cancer. Previous studies showed that inhibition or depletion of NAT1 in breast cancer cells diminishes anchorage-independent growth in culture, suggesting that NAT1 contributes to breast cancer growth and metastasis. To further investigate the contribution of NAT1 to growth and cell invasive/migratory behavior, we subjected parental and NAT1 knockout (KO) breast cancer cell lines (MDA-MB-231, MCF-7, and ZR-75-1) to multiple assays.