Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites
Abstract
:1. Introduction
2. Experimental Design
2.1. Study Design and Ethics
2.2. Study Procedure
2.3. Method for Estimating Concentrations of Serum Paracetamol and Its Metabolites
2.4. Genotyping of Genetic Polymorphisms
2.5. Statistical Analysis
3. Results
3.1. Demographic Characteristics
3.2. Genetic Polymorphisms
3.3. Paracetamol and Paracetamol Metabolite Concentrations
4. Discussion
4.1. Key Findings
4.2. Comparison with the Existing Literature
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variables | Values |
---|---|
Age (years) | 49 (21–91) |
Male:Female (n) | 82:68 |
Body weight (kg) | 75 (43.6–166.7) |
Serum total protein (g/L) | 64 (31–95) |
Serum albumin (g/L) | 35 (18–53) |
Serum bilirubin (mg/dl) | 10 (2–265) |
Serum alkaline phosphatase (IU/L) | 98 (34–513) |
Serum alanine transaminase (IU/L) | 23 (8–2835) |
Serum gamma-glutamyl transaminase (IU/L) | 36 (6–650) |
Serum creatinine (µmol/L) | 113 (15–1857) |
SNPs | P (μM) | PG (μM) | PS (μM) | P/PG | P/PS | PG/PS | |
---|---|---|---|---|---|---|---|
CYP2E1*5B | GG | 320.9 (0–2745.2) | 0.6 (0.1–6.8) | 0.4 (0.1–31.3) | 636.5 (64.8–6201.6) | 909.2 (34.8–6949.9) | 1.2 (0–19) |
GC | 337.4 (86–740.9) | 0.5 (0.1–1.9) | 0.5 (0.1–5.2) | 705 (306.5–3568.6) | 524 (95–4931.2) | 1.1 (0.2–4.8) | |
CC | 486.2 (205.1–767.3) | 1.1 (0.3–1.9) | 3 (0.6–5.3) | 560.9 (399.7–722.1) | 233 (144.5–321.4) | 0.4 | |
p-values | 0.8 | 0.5 | 0.3 | 0.8 | 0.1 | 0.1 | |
CYP1A2*C | AA | 357.2 (105.8–1587.6) | 0.7 (0.2–1.9) | 1.1 (0.1–6) | 604.2 (107.3–1578.1) | 416.7 (71.5–2898.7) | 0.7 (0.2–4.8) |
AG | 387 (125.7–740.9) | 0.4 (0.2–1.4) | 0.4 (0.2–5.2) | 823.6 (306.5–1579.1) | 956.6 (110.6–2205) | 1 (0.2–4.6) | |
GG | 297.7 (0–2745.2) | 0.6 (0.1–6.8) | 0.4 (0.1–31.3) | 612.5 (64.8–6201.6) | 800 (34.8–5277.1) | 1.3 (0–19) | |
p-values | 0.7 | 0.3 | 0.06 | 0.3 | 0.2 | 0.2 | |
CYP3A4*3 | AA | 344 (0–2745.2) | 0.6 (0.1–6.8) | 0.4 (0.1–31.3) | 636.5 (64.8–6201.6) | 802.4 (34.8–6949.9) | 1.2 (0–19) |
AG | 393.6 (125.7–707.8) | 0.5 (0.2–1.2) | 0.6 (0.2–5.2) | 662.9 (306.5–1579.1) | 457.8 (71.5–2898.7) | 0.7 (0.2–4.8) | |
p-values | 0.8 | 0.6 | 0.4 | 0.8 | 0.2 | 0.07 | |
CYP2E1*2 | GG | 330.8 (0–2745.2) | 0.6 (0.1–6.8) | 0.4 (0.1–31.3) | 637.5 (64.8–6201.6) | 822.8 (34.8–6949.9) | 1.2 (0–19) |
GA | 423.4 (125.7–992.3) | 0.4 (0.2–1.4) | 0.6 (0.2–2.5) | 836.3 (306.5–1579.1) | 460 (203.4–2898.7) | 0.7 (0.2–4.8) | |
p-values | 0.7 | 0.7 | 0.6 | 0.3 | 0.6 | 0.2 | |
CYP1A2*3 (GG) | 357.2 (0–2745.2) | 0.6 (0.1–6.8) | 0.4 (0.1–31.3) | 695.6 (64.8–6201.6) | 804.7 (34.8–6949.9) | 1.2 (0–19) | |
CYP1A2*1K | CC | 320.9 (0–2745.2) | 0.6 (0.1–6.8) | 0.4 (0.1–31.3) | 668.2 (64.8–6201.6) | 851.8 (34.8–5277.1) | 1.3 (0–19) |
CT | 403.5 (125.7–2745.2) | 0.5 (0.2–2.4) | 0.6 (0.2–3.1) | 703.7 (306.5–2385.1) | 510.6 (71.5–6949.9) | 0.7 (0.2–10.4) | |
TT | 539.1 (310.9–767.3) | 1.1 (0.3–1.9) | 3.2 (1.1–5.3) | 793.2 (399.7–1186.7) | 216.9 (144.5–289.2) | 0.3 (0.2–0.4) | |
p-values | 0.7 | 0.8 | 0.07 | 0.9 | 0.1 | 0.05 * | |
CYP1A2*6 | CC | 310.9 (112.5–1845.6) | 0.5 (0.1–4.5) | 0.4 (0.1–31.3) | 722.1 (64.8–6201.6) | 1016.6 (34.8–5277.1) | 1.3 (0–19) |
CT | 568.9 (178.6–992.3) | 0.8 (0.4–1.9) | 1.4 (0.3–2.7) | 504.4 (323.6–1190.1) | 514.9 (71.5–1378.1) | 1.2 (0.2–2.5) | |
TT | 767.3 | 1.9 | 5.3 | 399.7 | 144.5 | 0.4 | |
p-values | 0.06 | 0.04 * | 0.008 * | 0.3 | 0.05 * | 0.2 | |
CYP3A4*2 | AA | 310.9 (0–2745.2) | 0.5 (0.1–10.8) | 0.4 (0.1–31.3) | 695.6 (64.8–6201.6) | 840.8 (18.5–6949.9) | 1.2 (0–20.3) |
AG | 992.3 | 1.4 | 1.93 | 703.7 | 514.9 | 0.7 | |
p-values | 0.2 | 0.2 | 0.2 | 0.9 | 0.7 | 0.6 | |
CYP3A5*7 | Wild | 314.2 (0–2745.2) | 0.5 (0.1–10.8) | 0.4 (0.1–31.3) | 697.2 (64.8–6201.6) | 831.8 (18.5–6949.9) | 1.2 (0–20.3) |
Heterozygous | 383.7 (238.1–1772.8) | 0.5 (0.2–3.1) | 0.4 (0.1–2.2) | 835.2 (566.4–1591.8) | 1983.4 (370.4–5277.1) | 1.7 (0.3–9) | |
p-values | 0.5 | 0.8 | 0.4 | 0.4 | 0.2 | 0.5 | |
CYP3A5*11(Wild) | 314.2 (0–2745.2) | 0.5 (0.1–10.8) | 0.4 (0.1–31.3) | 697.2 (64.8–6201.6) | 831.8 (18.5–6949.9) | 1.2 (0–20.3) | |
CYP2D6*10 | 1/1 | 271.2 (238.1–317.5) | 0.2 (0.1–0.3) | 0.4 (0.1–0.8) | 1273.5 (1114.1–3568.6) | 2656.9 (382.6–4931.2) | 0.9 (0.3–1.4) |
1/2 | 258 (119.1–1091.5) | 0.3 (0.1–1.2) | 0.5 (0.1–31.3) | 816.4 (306.5–6201.6) | 356 (34.8–3166.8) | 0.6 (0–2.7) | |
2/2 | 231.5 (0–2745.2) | 0.6 (0.1–6.8) | 0.7 (0.1–8.6) | 484.5 (64.8–2367.1) | 392.1 (18.5–4378.3) | 0.7 (0.1–19) | |
p-values | 0.8 | 0.01 * | 0.4 | 0.008 * | 0.5 | 0.9 | |
CYP3A4*1B | TT | 244.8 (0–2745.2) | 0.5 (0.1–6.8) | 0.7 (0.1–31.3) | 536.4 (64.8–6201.6) | 387.4 (18.5–4931.2) | 0.7 (0–19) |
CT | 238.2 (145.5–648.3) | 0.3 (0.2–0.8) | 0.4 (0.1–2.5) | 895.7 (323.6–1591.8) | 677.6 (71.5–3166.8) | 0.7 (0.2–2.1) | |
CC | 205.1 | 0.51 | 1.3 | 402.9 | 156.3 | 0.4 | |
p-values | 0.9 | 0.5 | 0.4 | 0.4 | 0.4 | 0.8 |
Paracetamol Metabolites and Their Ratios | SNPs | ||
---|---|---|---|
CYP1A2*1K | CYP1A2*6 | CYP2D6*10 | |
PG | 0.6 [0.4–0.7] | 0.7 [0.6–0.9] * | 0.8 [0.6–1] * |
PS | 0.7 [0.5–0.8] * | 0.8 [0.7–0.9] * | 0.7 [0.3–1] |
P/PG | 0.5 [0.3–0.7] | 0.4 [0.2–0.5] | 0.1 [0.1–0.2] |
P/PS | 0.4 [0.2–0.5] | 0.3 [0.1–0.5] | 0.3 [0.1–0.6] |
PG/PS | 0.3 [0.2–0.5] | 0.3 [0.2–0.5] | 0.5 [0.1–0.9] |
Paracetamol, Paracetamol Metabolites and Their Ratios | Renal Dysfunction (n = 50) | No Renal Dysfunction (n = 100) | p-Values |
---|---|---|---|
P | 509.4 (112.5–2745.2) | 264.6 (0–2745.2) | <0.001 * |
PG | 0.8 (0.1–4.5) | 0.4 (0.1–10.8) | <0.001 * |
PS | 0.3 (0.1–4.6) | 0.6 (0.1–31.3) | 0.007 * |
P/PG | 625.2 (92.3–2385.1) | 711.4 (64.8–6201.6) | 0.7 |
P/PS | 1481.9 (78.1–6949.9) | 441.6 (18.5–4931.2) | <0.001 * |
PG/PS | 2 (0.2–20.3) | 0.7 (0–19) | <0.001 * |
Paracetamol, paracetamol metabolites and their ratios | ALI (n = 16) | No ALI (n = 134) | p-values |
P | 363.8 (119.1–972.4) | 314.2 (0–2745.2) | 0.7 |
PG | 0.5 (0.1–1.9) | 0.5 (0.1–10.8) | 0.9 |
PS | 0.3 (0.1–3.2) | 0.5 (0.1–31.3) | 0.9 |
P/PG | 617 (115.9–2467.8) | 851.8 (38.5–3262.2) | 0.7 |
P/PS | 851.8 (38.5–3262.2) | 813.8 (18.5–6949.9) | 0.9 |
PG/PS | 1.1 (0.2–4.6) | 1.2 (0–20.3) | 0.9 |
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Sridharan, K.; Qader, A.M.; Hammad, M.; Jassim, A.; Diab, D.E.; Abraham, B.; Hasan, H.M.S.N.; Pasha, S.A.A.; Shah, S. Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites. Metabolites 2022, 12, 1235. https://doi.org/10.3390/metabo12121235
Sridharan K, Qader AM, Hammad M, Jassim A, Diab DE, Abraham B, Hasan HMSN, Pasha SAA, Shah S. Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites. Metabolites. 2022; 12(12):1235. https://doi.org/10.3390/metabo12121235
Chicago/Turabian StyleSridharan, Kannan, Ali Mohamed Qader, Mustafa Hammad, Anfal Jassim, Diab Eltayeb Diab, Betsy Abraham, Hasan M. S. N. Hasan, Sheikh Abdul Azeez Pasha, and Shamik Shah. 2022. "Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites" Metabolites 12, no. 12: 1235. https://doi.org/10.3390/metabo12121235