CYP2C19 pharmacogenetics in advanced cancer: compromised function independent of genotype

CYP2C19 is a drug-metabolising enzyme involved in the metabolism of a number of chemotherapeutic agents including cyclophosphamide. Variants of the CYP2C19 gene result in a loss of function polymorphism, which affects approximately 3% of the Caucasian population. These individuals are poor metabolisers (PM) of a wide range of medications including omeprazole (OMP). In healthy subjects PM can be identified through homozygous variant genotype. However, a discordance between CYP2C19 genotype and phenotype has been reported previously in a small study of cancer patients. To investigate whether CYP2C19 activity was decreased in patients with advanced cancer, CYP2C19 genotype was determined in 33 advanced cancer patients using PCR-RFLP analysis for the two important allelic variants (*2,681G>A and *3,636G>A) and the activity of the enzyme was evaluated using the CYP2C19 probe drug OMP. The activity of the drug-metabolising enzyme CYP2C19 was severely compromised in advanced cancer patients, resulting in a PM status in 37% of the patients who had normal genotype. This is significantly (P<0.0005) higher than that would be predicted from the genotypic status of these patients. There was no evidence of a correlation between compromised CYP2C19 activity and any of the proinflammatory cytokines or acute phase response proteins studied. However, there was preliminary evidence of an association between PM status and low body mass (P=0.03). There is increasing interest in using pharmacogenetics to ‘individualise medicine', however, the results of this study indicate that in a cancer population genotyping for CYP2C19 would significantly underestimate the number of phenotypic PM of drugs, such as cyclophosphamide, which may be metabolised by this enzyme

(dipyrone) in rats

The effects of acetylsalicylate and metamizol on spinal monosynaptic reflexes were tested in spinal rats. Adult rats were anesthetized with ketamine, artificially ventilated, and spinalized at the CI level. A laminectomy was performed in the lumbosacral region. Following electrical stimulation of the sciatic nerve by single pulses, the reflex potentials were recorded from the ipsilateral L5 ventral root. Acetylsalicylate was administered orally via nasogastric tube and metamizol intramuscularly. Acetylsalicylate (50 and 100 mg/kg) and metamizol (15 mg/kg) significantly decreased the amplitude of the reflex response (p < 0.05). But the 10-mg/kg metamizol dose did not significantly decrease the amplitude of the reflex response. The cyclooxygenase products of arachidonic acid may play an important role in regulating the reflex potential. Copyright (C) 2003 S. Karger AG, Basel

Comparison of the effects on spinal reflexes of acetylsalicylate and metamizol in spinalized and normal rats.

The effects of nonsteroidal antiinflammatory drugs, acetylsalicylate and metamizol, on spinal monosynaptic reflexes were investigated in spinalized and normal rats. Adult rats (n=36) weighing 150-200 g were anesthetized with ketamine and artificially ventilated. Half of rats were spinalized at C1 level. A laminectomy was performed in the lumbosacral region. Following electrical stimulation of the sciatic nerve by single pulses, reflex potentials were recorded from the ipsilateral L5 ventral root. Acetylsalicylate was administered orally (100 mg/kg for both spinalized and normal rats). Metamizol was administered intramuscularly (15 mg/kg for both spinalized and normal rats). These drug administrations significantly decreased the amplitude of reflex response in all groups (p < 0.05). These data verify that observed inhibition by acetylsalicylicate and metamizol may be at the level of spinal cord. Also we suggested that the cyclooxygenase products of arachidonic acid may play an important role in regulating the reflex potential

Inhibition of spinal reflexes by acetylsalicylate and metamizol (dipyrone) in rats.

The effects of acetylsalicylate and metamizol on spinal monosynaptic reflexes were tested in spinal rats. Adult rats were anesthetized with ketamine, artificially ventilated, and spinalized at the C1 level. A laminectomy was performed in the lumbosacral region. Following electrical stimulation of the sciatic nerve by single pulses, the reflex potentials were recorded from the ipsilateral L5 ventral root. Acetylsalicylate was administered orally via nasogastric tube and metamizol intramuscularly. Acetylsalicylate (50 and 100 mg/kg) and metamizol (15 mg/kg) significantly decreased the amplitude of the reflex response (p < 0.05). But the 10-mg/kg metamizol dose did not significantly decrease the amplitude of the reflex response. The cyclooxygenase products of arachidonic acid may play an important role in regulating the reflex potential

Association of a genetic polymorphism of the alcohol-metabolizing enzyme ADH1C with alcohol dependence: results of a case-control study.

OBJECTIVE: Alcohol dependence causes serious problems which may be influenced by genetic factors associated with alcohol metabolism. The aim was to investigate the allelic and genotypic difference in distribution of a polymorphism in alcohol dehydrogenase 1C gene (ADH1C) between alcohol-dependent individuals and controls, and to examine if these genotypes were associated with the age at which the patient became alcohol-dependent. METHODS: We conducted a case-control study including 90 alcohol-dependent cases and 100 historic controls. The genomic DNA was isolated and the alleles were analyzed with an RFLP. RESULTS: The ADH1C*1 allele frequencies were 0.89 (95% CI 0.84-0.91) in controls and 0.68 (95% CI 0.61-0.74) in alcohol-dependent patients. The frequencies of the ADH1C*2 allele were 0.11 (95% CI 0.07-0.14) and 0.32 (95% CI 0.25-0.38) among controls and alcohol-dependent patients, respectively (p < 0.0001). The ADH1C*1/*1 genotype frequency was significantly higher in the control group (77%) compared to that of the alcohol-dependents (51%, p < 0.0001). The ADH1C*1/*2 genotype frequency was significantly lower in the control group (23%) compared to that of the alcohol-dependents (42%, p < 0.0001). We obtained no statistically significant difference among the ADH1C genotype groups regarding age. CONCLUSIONS: These findings suggest that a significantly higher presence of ADH1C*2 allele is associated with alcohol dependence in a Turkish population. Studies with other related polymorphisms are needed to more precisely estimate the association of alcohol dependence with ADH1C

Association of a Genetic Polymorphism of the Alcohol-Metabolizing Enzyme

Objective: Alcohol dependence causes serious problems which may be influenced by genetic factors associated with alcohol metabolism. The aim was to investigate the allelic and genotypic difference in distribution of a polymorphism in alcohol dehydrogenase 1C gene (ADH1C) between alcohol-dependent individuals and controls, and to examine if these genotypes were associated with the age at which the patient became alcohol-dependent. Methods: We conducted a case-control study including 90 alcohol-dependent cases and 100 historic controls. The genomic DNA was isolated and the alleles were analyzed with an RFLP. Results: The ADH1C*1 allele frequencies were 0.89 (95% CI 0.84-0.91) in controls and 0.68 (95% CI 0.61-0.74) in alcohol-dependent patients. The frequencies of the ADH1C*2 allele were 0.11 (95% CI 0.07-0.14) and 0.32 (95% CI 0.25-0.38) among controls and alcohol-dependent patients, respectively (p < 0.0001). The ADH1C*1/*1 genotype frequency was significantly higher in the control group (77%) compared to that of the alcohol-dependents (51%, p < 0.0001). The ADH1C*1/*2 genotype frequency was significantly lower in the control group (23%) compared to that of the alcohol-dependents (42%, p < 0.0001). We obtained no statistically significant difference among the ADH1C genotype groups regarding age. Conclusions: These findings suggest that a significantly higher presence of ADH1C*2 allele is associated with alcohol dependence in a Turkish population. Studies with other related polymorphisms are needed to more precisely estimate the association of alcohol dependence with ADH1C. Copyright (C) 2012 S. Karger AG, Base