Properties of Benzpyrene Hydroxylase from Human Liver and Comparison with the Rat, Rabbit and Guinea-pig Enzymes

Pelkonen, Olavi; Kaltiala, Eero H.; Kärki, Niilo T.; Jalonen, Kari; Pyörälà, Kalevi

doi:10.3109/00498257509056120

Cited by 28 publications

(8 citation statements)

References 18 publications

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“…see Pelkonen, 1976;Pelkonen et al, 1984;Vahakangas et al, 1983). The few available studies with human tissues have not yielded definitive results (Boobis et al, 1980;Pelkonen et al, 1975;Vahakangas et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

The effect of cigarette smoking on 7‐ethoxyresorufin O‐deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies.

Pelkonen¹,

Pasanen²,

Kuha³

et al. 1986

Brit J Clinical Pharma

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1 Four cytochrome P-450 enzyme activities, 7-ethoxyresorufin O-deethylase (ERDE), coumarin 7-hydroxylase (CH), 7-ethoxycoumarin 0-deethylase (ECDE) and aryl hydrocarbon hydroxylase (AHH) were measured in human liver needle biopsy samples from smokers and non-smokers. Cigarette smoking was verified and quantitated by measuring plasma cotinine levels.3 Enzyme inhibitory monoclonal antibodies (MAb) to a 3-methylcholanthrene-induced (MAb 1-7-1) and phenobarbitone-induced (MAb 2-66-3) rat hepatic cytochrome P-450 were used to measure the contribution of MAb-defined, epitope-specific cytochromes P-450 to the total reaction measured for each of the above activities. 3 ERDE activity was significantly elevated in the livers of cigarette smokers, whereas AHH, CH or ECDE activities were not affected by cigarette smoking. No correlation was observed between plasma cotinine concentration and ERDE activity. 4 MAb 1-7-1 inhibited hepatic ERDE activity to a variable extent (from 0 to 65%), but had very little or no effect on AHH, CH or ECDE activities. The inhibitory effect of MAb 1-7-1 on ERDE activity was greater than 50% in the non-smokers. MAb 2-66-3 had no inhibitory effect on any of the enzyme activities studied. 5 In contrast to liver both ERDE and AHH on human placental microsomes from cigarette smokers were inhibited by MAb 1-7-1. The MAb 2-66-3 was without effect. 6 Cigarette smoking induces a form of P-450 in human liver, responsible for ERDE activity, that contains an epitope recognized by MAb 1-7-1. This form of cytochrome P-450 is insensitive to MAb 2-66-3 and is not contributing to AHH, CH or ECDE activities of human liver.

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Section: Discussionmentioning

confidence: 99%

The effect of cigarette smoking on 7‐ethoxyresorufin O‐deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies.

Pelkonen¹,

Pasanen²,

Kuha³

et al. 1986

Brit J Clinical Pharma

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“…Furthermore, Sabadie et al (1980) demonstrated that the ability of human liver to catalyse the formation of mutagenic metabolites from N-nitroso-N'-methylpiperazine, presumably P-450-catalyzed reaction, was much higher than that of rodent livers. However, a general opinion has been, that human hepatic P-450-linked monooxygenase activities are lower than those in rodent livers (Kuntzman et al, 1966;Nelson et al, 1971;Ackerman, 1972;Pelkonen et al, 1975Pelkonen et al, , 1977Boobis et al, 1980;von Bahr et al, 1980;Jakobsson et al, 1982). Possible explanations can be sought from two directions.…”

Section: Discussionmentioning

confidence: 99%

Coumarin 7‐hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons.

Pelkonen¹,

Ea²,

Ahokas³

1985

Brit J Clinical Pharma

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Coumarin 7‐hydroxylation and other cytochrome P‐450‐associated enzyme activities were studied in human liver biopsy homogenates and compared with activities in livers of other species. Coumarin 7‐hydroxylation is extraordinarily active in human liver biopsy samples in vitro. Activity is lower in mouse, rabbit or guinea pig liver and essentially absent in rat liver. Cytochrome P‐450 content and other associated enzyme activities were higher in animals. Coumarin 7‐hydroxylation is induced by phenobarbitone in mouse liver, but no significant increase was seen in human or rat liver after exposure to inducers. Correlations amongst coumarin 7‐hydroxylase, aryl hydrocarbon hydroxylase, 7‐ethoxycoumarin O‐deethylase and cytochrome P‐450 are statistically significant (r values from 0.56 to 0.73), but do not permit the conclusion, that the same P‐450 form catalyzes all the reactions studied. The correlations between coumarin hydroxylation and antipyrine half‐life or clearance are statistically significant, but not good enough for predictive purposes. Coumarin 7‐hydroxylase in human liver is inhibited by alpha‐ naphthoflavone, SKF 525A, metyrapone and aniline.

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“…There are indications that aryl hydrocarbon hydroxylase activity in liver biopsy samples from smokers is higher than that from nonsmokers (31). However, preferential inhibition of the hydroxylase in vitro shows (29) that the enzyme in human liver more closely resembles the control P450-associated enzyme in rat or mouse liver microsomes.…”

Section: Bp Metabolites Which Bind To Dna Generated By Human Liver MImentioning

confidence: 97%

Carcinogenic Benzo(a)pyrene Metabolites Bound to DNA: Metabolic Formation by Human Cultured Lymphocytes and by Human Liver Microsomes

Boobis¹,

Atlas²,

Nebert³

1978

Pharmacology

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Sonicates of human cultured lymphocytes metabolize (benzo(a)pyrene to at least two intermediates that bind covalently to deproteinized DNA in vitro. The major peak represents the 4,5-oxide bound to nucleoside(s). No correlation is found between ‘aryl hydrocarbon hydroxylase activity’ (or its inducibility) and benzo(a)pyrene metabolites generated by human lymphocytes and bound to DNA in vitro. Human liver microsomes produce in vitro at least six such reactive intermediates which, bound to deproteinized DNA nucleosides, are separable by chromatography. The major peak represents the 7,8-diol-9,10-epoxides bound to nucleoside(s): this highly reactive intermediate is believed to be one of the ultimate carcinogenic forms of benzo(a)pyrene.

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Properties of Benzpyrene Hydroxylase from Human Liver and Comparison with the Rat, Rabbit and Guinea-pig Enzymes

Cited by 28 publications

References 18 publications

The effect of cigarette smoking on 7‐ethoxyresorufin O‐deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies.

The effect of cigarette smoking on 7‐ethoxyresorufin O‐deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies.

Coumarin 7‐hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons.

Carcinogenic Benzo(a)pyrene Metabolites Bound to DNA: Metabolic Formation by Human Cultured Lymphocytes and by Human Liver Microsomes

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