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Biotransformation of caffeine, paraxanthine, theophylline, and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes.
Drug Metab Dispos. 1987 Mar-Apr; 15(2):237-49.DM

Abstract

The microsomal metabolism of caffeine and its primary dimethylxanthine metabolites, paraxanthine, theophylline, and theobromine, was investigated in 15 different human livers, including those from two known nonsmokers and one known smoker. At least two distinct enzymes with differing substrate affinities have the potential to catalyze most methylxanthine N-demethylations and C8-hydroxylations in vitro; however, at the low methylxanthine concentrations routinely encountered in vivo, participation by the high affinity site is expected to predominate. It appears that the high affinity enzyme is a polycyclic aromatic hydrocarbon-inducible isozyme of cytochrome P-450, based on competitive inhibition by 7-ethoxyresorufin and benzo[a]pyrene, and based on a significant (p less than 0.001) correlation between 7-ethoxyresorufin-O-deethylation and methylxanthine demethylation rates. alpha-Naphthoflavone inhibited all methylxanthine demethylations in excess of 80% in two high activity livers, whereas 8-hydroxylations were generally inhibited less. Kinetic analysis of paraxanthine 7-demethylation in four different liver preparations resulted in similar Km values of 1.2 +/- 0.5 mM (mean +/- SD), whereas Vmax values varied 8-fold, compatible with participation by the same high affinity isozyme. Notable was the high degree of inter-liver variation in metabolic rates, with the known smoker showing the second highest activity among a 20-fold range in paraxanthine demethylation rates, consistent with polycyclic aromatic hydrocarbon-related enzyme induction. Maximal inhibition of paraxanthine 8-hydroxylation by alpha-naphthoflavone left similar residual activities in the 15 liver preparations, indicating the presence of an enzyme activity that was not inducible. Furthermore, in low activity livers, more than 80% of paraxanthine 8-hydroxylation was mediated by an isozyme of cytochrome P-450 insensitive to inhibition by alpha-naphthoflavone. Our in vitro data show that the proportion of demethylation relative to hydroxylation products of paraxanthine correlate with 7-ethoxyresorufin O-deethylation rates. Taken together, the data provide a rationale for a potential in vivo marker of polycyclic aromatic hydrocarbon-inducible cytochrome P-450 activity based on a urinary metabolite ratio of paraxanthine 7-demethylation to 8-hydroxylation products after caffeine intake.

Authors

Campbell ME
No affiliation info available
Grant DM
No affiliation info available
Inaba T
No affiliation info available
Kalow W
No affiliation info available

MeSH

AdultBiotransformationCaffeineCytochrome P-450 Enzyme SystemEnzyme InductionFemaleHumansKineticsMaleMicrosomes, LiverMiddle AgedPolycyclic CompoundsTheobromineTheophyllineXanthines

Pub Type(s)

Journal Article

Language

eng

PubMed ID

2882985

Citation

Campbell, M E., et al. "Biotransformation of Caffeine, Paraxanthine, Theophylline, and Theobromine By Polycyclic Aromatic Hydrocarbon-inducible Cytochrome(s) P-450 in Human Liver Microsomes." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 15, no. 2, 1987, pp. 237-49.
Campbell ME, Grant DM, Inaba T, et al. Biotransformation of caffeine, paraxanthine, theophylline, and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes. Drug Metab Dispos. 1987;15(2):237-49.
Campbell, M. E., Grant, D. M., Inaba, T., & Kalow, W. (1987). Biotransformation of caffeine, paraxanthine, theophylline, and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 15(2), 237-49.
Campbell ME, et al. Biotransformation of Caffeine, Paraxanthine, Theophylline, and Theobromine By Polycyclic Aromatic Hydrocarbon-inducible Cytochrome(s) P-450 in Human Liver Microsomes. Drug Metab Dispos. 1987 Mar-Apr;15(2):237-49. PubMed PMID: 2882985.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biotransformation of caffeine, paraxanthine, theophylline, and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes. AU - Campbell,M E, AU - Grant,D M, AU - Inaba,T, AU - Kalow,W, PY - 1987/3/1/pubmed PY - 1987/3/1/medline PY - 1987/3/1/entrez SP - 237 EP - 49 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 15 IS - 2 N2 - The microsomal metabolism of caffeine and its primary dimethylxanthine metabolites, paraxanthine, theophylline, and theobromine, was investigated in 15 different human livers, including those from two known nonsmokers and one known smoker. At least two distinct enzymes with differing substrate affinities have the potential to catalyze most methylxanthine N-demethylations and C8-hydroxylations in vitro; however, at the low methylxanthine concentrations routinely encountered in vivo, participation by the high affinity site is expected to predominate. It appears that the high affinity enzyme is a polycyclic aromatic hydrocarbon-inducible isozyme of cytochrome P-450, based on competitive inhibition by 7-ethoxyresorufin and benzo[a]pyrene, and based on a significant (p less than 0.001) correlation between 7-ethoxyresorufin-O-deethylation and methylxanthine demethylation rates. alpha-Naphthoflavone inhibited all methylxanthine demethylations in excess of 80% in two high activity livers, whereas 8-hydroxylations were generally inhibited less. Kinetic analysis of paraxanthine 7-demethylation in four different liver preparations resulted in similar Km values of 1.2 +/- 0.5 mM (mean +/- SD), whereas Vmax values varied 8-fold, compatible with participation by the same high affinity isozyme. Notable was the high degree of inter-liver variation in metabolic rates, with the known smoker showing the second highest activity among a 20-fold range in paraxanthine demethylation rates, consistent with polycyclic aromatic hydrocarbon-related enzyme induction. Maximal inhibition of paraxanthine 8-hydroxylation by alpha-naphthoflavone left similar residual activities in the 15 liver preparations, indicating the presence of an enzyme activity that was not inducible. Furthermore, in low activity livers, more than 80% of paraxanthine 8-hydroxylation was mediated by an isozyme of cytochrome P-450 insensitive to inhibition by alpha-naphthoflavone. Our in vitro data show that the proportion of demethylation relative to hydroxylation products of paraxanthine correlate with 7-ethoxyresorufin O-deethylation rates. Taken together, the data provide a rationale for a potential in vivo marker of polycyclic aromatic hydrocarbon-inducible cytochrome P-450 activity based on a urinary metabolite ratio of paraxanthine 7-demethylation to 8-hydroxylation products after caffeine intake. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/2882985/Biotransformation_of_caffeine_paraxanthine_theophylline_and_theobromine_by_polycyclic_aromatic_hydrocarbon_inducible_cytochrome_s__P_450_in_human_liver_microsomes_ DB - PRIME DP - Unbound Medicine ER -