CYP1A2 activity, gender and smoking, as variables influencing the toxicity of caffeine

Carrillo, Juan Antonio Cabrera; Benı́tez, Julio

doi:10.1046/j.1365-2125.1996.35418.x

Cited by 103 publications

(52 citation statements)

References 10 publications

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“…It has consistently been demonstrated that females on average have a lower CYP1A2 activity than males. For example, females have higher drug concentrations than males both of the probe drug caeine [18] and of psychotropic CYP1A2 substrates such as clozapine [19] and olanzapine [20]. In contrast, females might have a somewhat higher CYP2D6 activity than males, although the dierence is negligible or close to negligible [21].…”

Section: Discussionmentioning

confidence: 88%

The major fluvoxamine metabolite in urine is formed by CYP2D6

Spigset¹,

Axelsson²,

Norström³

et al. 2001

Eur J Clin Pharmacol

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Objective: Previous studies have shown that uvoxamine is metabolized by CYP1A2 and CYP2D6, but there is no information on the impact the various CYP enzymes have on the dierent metabolic pathways of¯uvoxamine biotransformation. The present study was designed to investigate this issue. Methods: The major¯uvoxamine metabolite, the 5-demethoxylated carboxylic acid metabolite, was analyzed in urine from 50 healthy volunteers after intake of a single oral dose of 50 mg¯uvoxamine, and the formation clearance for the metabolite (CL m ) was calculated. Of the subjects, 28 were non-smoking CYP2D6 and CYP2C19 extensive metabolizers (EMs), 12 were smokers and were thus considered to have an induced CYP1A2 activity, 5 were CYP2D6 poor metabolizers (PMs), and 5 were CYP2C19 PMs. In 11 of the nonsmoking EMs, 200 mg caeine was given at another occasion in order to calculate oral caeine clearance as a measure of CYP1A2 activity. In addition, CL m was calculated in ten other subjects given increasing doses of uvoxamine for 4 weeks. Results: Oral clearance of¯uvoxamine was signi®cantly higher in smokers, and signi®cantly lower in CYP2D6 PMs than in non-smoking EMs. CL m was 78% lower in CYP2D6 PMs than in the EMs. Smoking and being a CYP2C19 PM did not in¯uence CL m . There was no signi®cant correlation between oral caeine clearance and CL m . CL m decreased with increasing¯uvoxamine dosage, but the decrease in oral clearance was even higher. Conclusion:These results indicate that CYP2D6 catalyzes the major metabolic pathway of¯uvoxamine, whereas CYP1A2 seems to catalyze other less important pathways. Both the CYP2D6 and the CYP1A2 pathways seem to be saturated in parallel with increasinḡ uvoxamine dosage.

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Section: Discussionmentioning

confidence: 88%

The major fluvoxamine metabolite in urine is formed by CYP2D6

Spigset¹,

Axelsson²,

Norström³

et al. 2001

Eur J Clin Pharmacol

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“…In addition, in vitro CYP1A2 activity towards phenacetin O-deethylation was observed here to be lower within the Chinese female samples than the Chinese male samples, but such a gender difference was not significant with the Caucasian samples. In earlier human studies, CYP1A2 activity towards caffeine metabolism appeared to be lower for women than men in Chinese [26] and Caucasians [27].…”

Section: Discussionmentioning

confidence: 99%

Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes

Yang

Niu

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The mean catalytic activities of CYP1A2, CYP2A6, CYP2D6, CYP2E1 and CYP3A4 in human liver microsomes (HLM) of Japanese origin were found to be lower than the corresponding mean values of Caucasian HLM, but the distribution patterns of data in these studies were not well addressed.• Interindividual variations in metabolic activities of Chinese HLM samples were reported for CYP1A2, CYP2C9, CYP2D6 and CYP3A4, but little is known about the difference in CYP activities between Chinese and Caucasian HLM samples.• The vast majority of the preceding studies were based on the measurement of metabolite formation rates at a certain fixed substrate concentration, rather than enzyme kinetic analyses.WHAT THIS STUDY ADDS• Significant differences in metabolic capability were observed for CYP1A2, CYP2C9, CYP2C19 and CYP2E1 with the median values lower for the Chinese HLM samples vs. the Caucasian samples, which were associated with differences in Michaelis constant or maximum velocity.• Despite negligible differences in metabolic capability for CYP2A6, CYP2B6, CYP2C8, CYP2D6 and CYP3A, Michaelis constant of CYP2B6 appeared to have a significant ethnic difference.AIM The most common causes of variability in drug response include differences in drug metabolism, especially when the hepatic cytochrome P450 (CYP) enzymes are involved. The current study was conducted to assess the differences in CYP activities in human liver microsomes (HLM) of Chinese or Caucasian origin.METHODS The metabolic capabilities of CYP enzymes in 30 Chinese liver microsomal samples were compared with those of 30 Caucasian samples utilizing enzyme kinetics. Phenacetin O‐deethylation, coumarin 7‐hydroxylation, bupropion hydroxylation, amodiaquine N‐desethylation, diclofenac 4′‐hydroxylation (S)‐mephenytoin 4′‐hydroxylation, dextromethorphan O‐demethylation, chlorzoxazone 6‐hydroxylation and midazolam 1′‐hydroxylation/testosterone 6β‐hydroxylation were used as probes for activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Mann‐Whitney U test was used to assess the differences.RESULTS The samples of the two ethnic groups were not significantly different in cytochrome‐b5 concentrations but were significantly different in total CYP concentrations and NADPH‐P450 reductase activity (P < 0.05). Significant ethnic differences in intrinsic clearance were observed for CYP1A2, CYP2C9, CYP2C19 and CYP2E1; the median values of the Chinese group were 54, 58, 26, and 35% of the corresponding values of the Caucasian group, respectively. These differences were associated with differences in Michaelis constant or maximum velocity. Despite negligible difference in intrinsic clearance, the Michaelis constant of CYP2B6 appeared to have a significant ethnic difference. No ethnic difference was observed for CYP2A6, CYP2C8, CYP2D6 and CYP3A.CONCLUSIONS These data extend our knowledge on the ethnic differences in CYP enzymes and will have implications for drug discovery and drug therapy for patients from different ethnic origins.

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“…Females were not included due to gender differences in caffeine consumption and metabolism (Carrillo and Benitez, 1996;Magkos and Kavouras, 2005). The study was approved by the medical ethical committee at Maastricht University academic hospital.…”

Section: Participantsmentioning

confidence: 99%