Metabolic activation of environmental carcinogens and mutagens by human liver microsomes

Shimada, Tsutomu; Okuda, Yasuko

doi:10.1016/0006-2952(88)90215-8

Cited by 45 publications

(5 citation statements)

References 18 publications

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“…These include proteins from the 3-methylcholanthrene-inducible family P4501A (5)(6)(7), the phenobarbital-inducible P450IlB subfamily (8,9), and P450IIC subfamily (10), the dexamethaxone-inducible P450IIIA family (11), and possibly P450s from the family P450IVB (8).…”

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confidence: 99%

“…The administration of polycyclic hydrocarbons induces predominantly 4-hydroxylation, forming aflatoxin Ml (AFM1), and to a much lesser extent epoxidation, whereas phenobarbital induces epoxidation and aflatoxin Q, (AFQ1) formation to approximately equal extents (12). In the case of human microsomes, Shimada and Okuda (11) concluded that constitutively expressed forms were probably involved in AFB1 activation. They excluded cytochromes from the P450IA and P45OIIB gene families, as antibodies raised against the rat homologues of these proteins did not inhibit AFB1 metabolism in human liver.…”

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confidence: 99%

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Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver.

Forrester¹,

Neal²,

Judah³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

165

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Liver cancer is a major cause of premature death in many areas of Africa and Asia and its incidence is strongly correlated with exposure to aflatoxin B1 (AFB1).Because AFB1 requires metabolic activation to achieve a biological response, there is a need for detailed knowledge of the mechanism of activation to assess individual risk. We have carried out an extensive study using a total of 19 human liver samples to determine the individual variability in the metabolism of the toxin to mutagenic or detoxification products and to identify the specific cytochrome P450 forms involved in these processes. Metabolism to the toxic 8,9-epoxide or to products mutagenic in the Ames test was found to exhibit very large individual variation. The rates of metabolic activation were highly correlated with both the level of proteins of the P450I1A gene family and with the total cytochrome P450 content of the microsomes. In agreement with this, antibodies reacting with P450IHA proteins were strong inhibitors of both

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confidence: 99%

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confidence: 99%

Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver.

Forrester¹,

Neal²,

Judah³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

165

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“…found to be saturating as judged by umu response at P-450 concentrations of 10-50 uM (10). The formation of DNA adducts by liver microsomes and HPLC assay of released AFB,-N7-Gua were based on procedures described by Essigman et al (5), using 1 ,uM P-450 and 20 AuM AFB1 in incubations and a period of 60 min (370C), during which the formation of DNA adducts was found to be linear with respect to time using rat liver microsomes.…”

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confidence: 99%

Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver.

Shimada

Guengerich

1989

Proc. Natl. Acad. Sci. U.S.A.

256

142

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In vitro studies with human liver indicate that the major catalyst involved in the bioactivation of the hepatocarcinogen aflatoxin B1 (AFB1) to its genotoxic 2,3-epoxide derivative is cytochrome P-45ONF (P-45ONF), a previously characterized protein that also catalyzes the oxidation of nifedipine and other dihydropyridines, quinidine, macrolide antibiotics, various steroids, and other compounds. Evidence was obtained using activation of AFB1 as monitored by umuC gene expression response in Salmonella typhimurium TA1535/pSK1002 and enzyme reconstitution, immunochemical inhibition, correlation of response with levels of P-450NF and nifedipine oxidase activity in different liver samples, stimulation of activity by 7,8-benzofavone, and inhibition of activity by troleandomycin. Similar results were obtained when levels of 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1 formed in DNA were measured. P-45ONF or a closely related protein also appears to be the major catalyst involved in the activation of aflatoxin G1 and sterigmatocystin, the latter compound being more genotoxic than AFB1 in these systems. Several drugs and conditions are known to influence the levels and activity of P-45ONF in human liver, and the activity of the enzyme can be estimated by noninvasive assays. These findings provide a test system for the hypothesis that a specific human disease state (liver cancer) is linked to the level of oxidative metabolism in populations in which aflatoxin ingestion is high.Aflatoxin B1 (AFB1) is one of the most potent hepatocarcinogens known, and environmental contamination by various aflatoxins is a serious problem in many parts of the world (for review, see ref. 1). The prototype AFB1 is not particularly biologically active in its native form, and oxidation is necessary for interaction with DNA and biological damage (1-6).Recently, a number of attempts have been made to link the incidence of various tumors in humans to levels of activity of specific drug-metabolizing enzymes (7-9). With regard to the specific forms of cytochrome P-450 involved in AFB1 activation, there is ambiguity in assignment of the involved rat liver P-450s in the literature (see refs. 9 and 10 and references therein) and these studies do not point clearly to human orthologs. If the form of human P-450 involved in aflatoxin bioactivation could be identified and appropriate in vivo assays could be devised in populations in which aflatoxin exposure is high (11), then the general hypothesis concerning cancer risk might be tested. In this report, we provide evidence that P-450NF, the previously characterized nifedipine oxidase (12), is the main catalyst of bioactivation of two major aflatoxins, AFB1 and AFG1, and the related naturally occurring carcinogen sterigmatocystin (STG). Levels of the enzyme vary widely among humans and can be readily monitored (13,14). MATERIALS AND METHODSHuman liver samples were obtained from organ donors through the Nashville Regional Organ Procurement Agency and microsomes were prepared. Human P-45ONF (12),...

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“…In contrast, 2-AA and AFB! are transformed to mutagens by this S9 frac tion suggesting that constitutive forms of cy tochrome P-450 are involved in the transfor mation of these two substances [11], Robertson and Birnbaum [12] suggested that the modification in mutagenic activation with age may be related to processes of matu ration rather than to senescence; our results, however, show that hepatic activation of AFBi and 2-AA not only increased until adulthood but declined in old age indicating that senescence can affect the biotransforma tion of xenobiotic substances. One may specu late that synthesis of the cytochrome P-450 involved is stimulated by intrinsic steroid hormones.…”

Section: Resultsmentioning

confidence: 99%

Effect of Age on the Ability of Rat Liver Tissues to Transform Chemical Promutagens to Mutagens

Hilali¹,

Crutzen-Fayt²,

Gerber³

et al. 1993

Gerontology

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Age-related changes in drug metabolism of the liver from male Lou rats were determined by measuring changes in the production of mutagens. Activation of aflatoxin B₁ (AFB₁), 2-aminoanthracene (2AA) and benzo[a]pyrene (B[a]P) to mutagenic derivatives was assayed using the Ames salmonella test system. The promutagens were incubated with tissue fractions isolated from rats ranging in age from 3 weeks to 18 months. Hepatic activation of AFB₁ and 2AA changes with age and is maximal from 4 to 10 months. In contrast, no significant modification with age was observed for the activation of B[a]P. It is concluded that the composition of different cytochrome P-450 fractions is modified with age thereby altering the specific ability to convert different promutagens to mutagens.

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Metabolic activation of environmental carcinogens and mutagens by human liver microsomes

Cited by 45 publications

References 18 publications

Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver.

Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver.

Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver.

Effect of Age on the Ability of Rat Liver Tissues to Transform Chemical Promutagens to Mutagens

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