Metabolic Activation of Pyrolysate Arylamines by Human Liver Microsomes; Possible Involvement of a P‐448‐H Type Cytochrome P‐450

Yamazoe, Yasushi; Abu‐Zeid, M. E.; Yamauchi, Kiyomi; Kato, Ryuichi

doi:10.1111/j.1349-7006.1988.tb01540.x

Cited by 45 publications

(26 citation statements)

References 32 publications

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“…Both activities were inhibited to the same extent by anti-human P-45OPA and by the specific P-450 inhibitors 7,8-benzoflavone and 2-[(2,4-dichloro-6-phenyl)phenoxy]ethylamine. Human liver microsomes also catalyzed the N-oxidation of 2-NA (12), Glu-P-1 (20), and IQ; each of these was strongly inhibited by anti-human P-45OPA. Interestingly, the rate of N-oxidation of these arylamines was about one-half the rate of that observed with ABP, which is regarded as the most potent of the arylamine human carcinogens (6); Trp-P-2 was poorly N-oxidized by human liver microsomes.…”

Section: Resultsmentioning

confidence: 99%

Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines.

Butler

Iwasaki

Guengerich

et al. 1989

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

568

327

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Aromatic amines are well known as occupational carcinogens and are found in cooked foods, tobacco smoke, synthetic fuels, and agricultural chemicals. For the primary arylamines, metabolic N-oxidation by hepatic cytochromes-P-450 is generally regarded as an initial activation step leading to carcinogenesis. The metabolic activation of 4-aminobiphenyl, 2-naphthylamine, and several heterocyclic amines has been shown recently to be catalyzed by rat cytochrome P-450ISF-G and by its human ortholog, cytochrome P-45OPA. We now report that human hepatic microsomal caffeine 3-demethylation, the initial major step in caffeine biotransformation in humans, is selectively catalyzed by cytochrome P-450PA. Caffeine 3-demethylation was highly correlated with 4-aminobiphenyl N-oxidation (r = 0.99; P < 0.0005) in hepatic microsomal preparations obtained from 22 human organ donors, and both activities were similarly decreased by the selective inhibitor, 7,8-benzoflavone. The rates of microsomal caffeine 3-demethylation, 4-aminobiphenyl Noxidation, and phenacetin O-deethylation were also significantly correlated with each other and with the levels of immunoreactive human cytochrome P 450PA. Moreover, a rabbit polyclonal antibody raised to human cytochrome P-450PA was shown to inhibit strongly all three of these activities and to inhibit the N-oxidation of the carcinogen 2-naphthylamine and the heterocyclic amines, 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole and 2-amino-3-methylimidazo[4,5-fquinoline. Human liver cytochrome P-45OPA was also shown to catalyze caffeine 3-demethylation, 4-aminobiphenyl N-oxidation, and phenacetin 0-deethylation. Thus, estimation of caffeine 3-demethylation activity in humans may be useful in the characterization of arylamine N-oxidation phenotypes and in the assessment of whether or not the hepatic levels of cytochrome P-450PA, as affected by environmental or genetic factors, contribute to interindividual differences in susceptibility to arylamine-induced cancers.The carcinogenicity of arylamines has been well established in both humans and experimental animals (1). Humans are frequently exposed to arylamines such as 4-aminobiphenyl (ABP), 2-naphthylamine (2-NA), and o-toluidine in mainstream and sidestream cigarette smoke (2) and to mutagenic and carcinogenic heterocyclic arylamines in cooked foods (3). Arylamines are also found in coal-and shale-derived oils (4) and in agricultural chemicals (5), and they are used in a variety of industrial processes (1,6,7).Metabolic N-oxidation of primary arylamines, catalyzed by hepatic cytochromes P-450 (P-450s), is a critical initial activation step leading to carcinogenesis (reviewed in refs. 8 and 9). ¶ Studies with purified rat and rabbit P-450s have shown high specificity for the N-oxidation of 2-acetylaminofluorene, 2-NA, ABP, and several heterocyclic amines to their proximate carcinogenic and/or mutagenic forms by the P450IA2 gene products in various species (8)(9)(10)(11)(12)(13)(14)(15). In humans, the orthologous P-450 (16, 17), termed P-45...

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Section: Resultsmentioning

confidence: 99%

Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines.

Butler

Iwasaki

Guengerich

et al. 1989

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

568

327

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“…Adult BALB/CAnN X DBA/ 2NF1 (CDF1) mice, Hartley guinea pig, and New Zealand white rabbits were obtained from Clea Japan, Tokyo; Syrian golden hamsters were from Tokyo Laboratory Animal Sciences. The source of human livers was the same as described previously (26). Sulfation Assay-Sulfation of T, and its analogs was determined by the method of Sekura et aL (20) with minor modifications: Briefly, the incubation mixture consisted of 250 /zM Tris-HCl (pH 7.9), 5 mM mercaptoethanol, 50 /*M substrate, 200//M "S-PAPS, and 0.5^g/ml cytosolic protein in a total volume of 50//I.…”

Section: Chemicals-35-diiodothyroninementioning

confidence: 99%

Hepatic Triiodothyronine Sulfation and Its Regulation by Growth Hormone and Triiodothyronine in Rats1

Gong

Murayama

Yamazoe

et al. 1992

The Journal of Biochemistry

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The regulatory mechanism of cytosolic sulfation of T3 has been studied in rat liver. Sulfation of T3 is sexually differentiated in adult rats of Sprague-Dawley (SD), Fisher 344, and ACI strains. In SD strain, the male animals showed 4 times higher sulfating activity than did the females. The specific activity was decreased by hypophysectomy of male adult rats, but was not affected in the females. Thus, the sex-difference was abolished in the hypophysectomized condition. Supplement of human GH intermittently twice daily for 7 days, to mimic the male secretory pattern, increased T3 sulfating activity in both sexes of hypophysectomized rats, whereas continuous infusion to mimic a female secretory pattern had no appreciable effect. Cytosolic sulfation of T3 was decreased by 25 to 30% by thyroidectomy or propylthiouracil treatment of male adult rats, and was restored by the supplementation of T3 (50 micrograms/kg daily for 7 days) to thyroidectomized rats. Administration of T3 in hypophysectomized rats almost completely restored the sulfating activity in the males and increased the activity in the females. Cytosolic T3 sulfation was inhibited by the addition of known inhibitors of phenol sulfotransferase, pentachlorophenol or 2,6-dichloro-4-nitrophenol. These results indicate a role of pituitary GH in hepatic sulfation of thyroid hormones in rats. The data obtained also raise the possibility that GH may modify the effect of thyroid hormones on the pituitary by a feed-back mechanism through changing the level of a sex-dominant phenol sulfotransferase(s) in rat livers. T3 was also sulfated in hepatic cytosols of mouse, hamster, rabbit, dog, monkey, and human.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…The preparation of microsomes from human liver samples from 10 Japanese subjects was performed as described previously (Yamazoe et al, 1988). Microsomal suspensions were stored at Ϫ80°C until use.…”

Section: Methodsmentioning

confidence: 99%

DETECTION OF A NEW N-OXIDIZED METABOLITE OF FLUTAMIDE, N-[4-NITRO-3-(TRIFLUOROMETHYL)PHENYL]HYDROXYLAMINE, IN HUMAN LIVER MICROSOMES AND URINE OF PROSTATE CANCER PATIENTS

Goda

Nagai²,

Akiyama³

et al. 2006

Drug Metab Dispos

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Metabolic Activation of Pyrolysate Arylamines by Human Liver Microsomes; Possible Involvement of a P‐448‐H Type Cytochrome P‐450

Cited by 45 publications

References 32 publications

Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines.

Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines.

Hepatic Triiodothyronine Sulfation and Its Regulation by Growth Hormone and Triiodothyronine in Rats1

DETECTION OF A NEW N-OXIDIZED METABOLITE OF FLUTAMIDE, N-[4-NITRO-3-(TRIFLUOROMETHYL)PHENYL]HYDROXYLAMINE, IN HUMAN LIVER MICROSOMES AND URINE OF PROSTATE CANCER PATIENTS

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