Studies on the induction of CO-binding pigments in liver microsomes by phenobarbital and 3-methylcholanthrene

Alvares, Alvito P.; Schilling, G.; Levin, Wayne; Kuntzman, R.

doi:10.1016/0006-291x(67)90515-3

Cited by 318 publications

(35 citation statements)

References 6 publications

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“…Our observation that BA as well as MC induced microsomal cytochrome P-448 (Fig. 2), while uninduced and phenobarbital-induced microsomes contained cytochrome P-450, complemented previous reports on the differing inductive effects of polycyclic hydrocarbons and phenobarbital (3,7,(9)(10)(11).…”

supporting

confidence: 78%

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Metabolic activation of aromatic hydrocarbons in purified rat liver nuclei: induction of enzyme activities and binding to DNA with and without monooxygenase-catalyzed formation of active oxygen.

Rogan¹,

Mailander²,

Cavalieri³

1976

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

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supporting

confidence: 78%

“…specificity by some hydrocarbons (3)(4)(5)(6)(7)(8)(9)(10)(11). Carcinogenic hydrocarbons' may enhance their own metabolism by inducing enzymes which show specificity for the hydrocarbon.…”

mentioning

confidence: 99%

Metabolic activation of aromatic hydrocarbons in purified rat liver nuclei: induction of enzyme activities and binding to DNA with and without monooxygenase-catalyzed formation of active oxygen.

Rogan¹,

Mailander²,

Cavalieri³

1976

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

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“…Early work in rat liver had shown that PAH treatment caused a shift in the carbon monoxide (CO)-reduced cytochrome P450 (P450) spectrum from 450 to 448 nm (Alvares et al, 1967;Kuntzman et al, 1968). Subsequently, AHH induction in the Ah-responsive but not Ah-nonresponsive mouse liver was demonstrated to be associated with a hypsochromic spectral shift in CO-reduced cytochrome P450, indicating the formation of a new form of induced P450 protein (Nebert, 1970;Gielen et al, 1972).…”

Section: Resultsmentioning

confidence: 99%

Oral Benzo[a]pyrene: Understanding Pharmacokinetics, Detoxication, and Consequences—Cyp1Knockout Mouse Lines as a Paradigm

et al. 2013

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Benzo [a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH); this ubiquitous environmental carcinogenic agent is found in tobacco smoke, charcoal-grilled foods, and PAH-contaminated surfaces of roofs, playgrounds, and highways. Cytochrome P450 1 wild-type, Cyp1a2(2/2), Cyp1b1(2/2), or Cyp1a2/1b1(2/2) knockouts, and mice with Cyp1a1 expression deleted in hepatocytes can ingest large oral BaP doses (125 mg/kg/d) without apparent toxicity. Cyp1a1(2/2) and Cyp1a1/1a2(2/2) knockouts and mice with Cyp1a1 expression deleted in gastrointestinal (GI) tract epithelial cells develop immunotoxicity and die within 32 days, indicating that GI tract inducible CYP1A1 is absolutely required for detoxication of oral BaP. Cyp1a1/1b1(2/2) and Cyp1a1/1a2/1b1(2/2) mice are rescued from immunosuppression and early death due to absent metabolic activation of BaP by CYP1B1 in immune cells. Ten-fold lower oral BaP doses result in adenocarcinoma of the proximal small intestine (PSI) in Cyp1a1(2/2) mice; Cyp1a1/1b1(2/2) double-knockout mice show no PSI cancer but develop squamous cell carcinoma of the preputial gland duct (PGD). BaP-metabolizing CYP1B1 in the PSI and CYP3A59 in the PGD are the most likely candidates to participate in tumor initiation in the epithelial cells of these two tissues; oncogenes and tumor-suppressor genes upregulated and downregulated during tumorigenesis are completely different between these tissues. This "oral BaP Cyp1" mouse paradigm represents a powerful teaching tool, showing that gene-environment interactions depend on route-of-administration: the same oral, but not intraperitoneal, BaP exposure leads to dramatic differences in target-organ toxicity and tumor type as a function of dose and Cyp1 genotype.

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“…Recent studies have suggested the existence of more than two enzymes which metabolize the drugs (8,9). With the mixed-function oxidase for hydroxylation, the difference of the terminal oxidase or the variety of binding sites of type I compounds may also cause a complicated inhibition of the hydroxylation of type 11 compounds.…”

Section: Discussionmentioning

confidence: 99%

“…Cytochrome(s) P-450 plays a critical role as the terminal oxidase in the metabolism of drugs, steroids and heme (5)(6)(7). It is generally accepted that the hepatic drug-metabolizing enzyme system has few specificities for substrates but recent studies have suggested the existence of more than two microsomal enzymes which metabolize the drugs (8,9).<BR> On the other hand, the addition of various substrates of microsomal mixed-function oxidase system to aerobic liver microsomes causes two types of spectral change. One class of spectral change (termed type I) is characterized by the appearance of a trough at 420 mμ…”

mentioning

confidence: 99%

Effect of Type I Compounds on P-Hydroxylation of Aniline in Vitro

et al. 1972

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During the past fifteen years, it has become evident that a variety of lipid soluble drugs such as aniline, aminopyrine and hexobarbital are oxidized by NADPH-dependent enzymes in hepatic microsomes (1-4). Cytochrome(s) P-450 plays a critical role as the terminal oxidase in the metabolism of drugs, steroids and heme (5-7). It is generally accepted that the hepatic drug-metabolizing enzyme system has few specificities for substrates but recent studies have suggested the existence of more than two microsomal enzymes which metabolize the drugs (8, 9).
On the other hand, the addition of various substrates of microsomal mixed-function oxidase system to aerobic liver microsomes causes two types of spectral change. One class of spectral change (termed type I) is characterized by the appearance of a trough at 420 mμand an absorption peak at 385 mμ. Aminopyrine, hexobarbital, chlorpromazine, SKF 525-A and DDT cause type I spectral change. Another class of spectral change (termed type II) is characterized by the appearance of a trough at 392 mμ and an absorption peak at 430 mμ. Aniline, nicotinamide, pyridine and p-aminophenol cause type II spectral change (10).
Drug interaction with endoplasmic reticulum occurs not only to constitute enzyme substrate complex but also to modify the physical properties, amounts, composition and turnover of constitutive membrane components (11). At present aniline is thought to bind to the CO-binding site of cytochrome P-450, whereas aminopyrine or hexobarbital is thought to bind to the lipids of the endoplasmic reticulum or hydrophobic region cytochrome P-450 (12).
The present paper concerns the effects of type I binders such as aminopyrine, hex obarbital and chlorpromazine on p-hydroxylation of aniline in vitro. METHODS Male

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Studies on the induction of CO-binding pigments in liver microsomes by phenobarbital and 3-methylcholanthrene

Cited by 318 publications

References 6 publications

Metabolic activation of aromatic hydrocarbons in purified rat liver nuclei: induction of enzyme activities and binding to DNA with and without monooxygenase-catalyzed formation of active oxygen.

Metabolic activation of aromatic hydrocarbons in purified rat liver nuclei: induction of enzyme activities and binding to DNA with and without monooxygenase-catalyzed formation of active oxygen.

Oral Benzo[a]pyrene: Understanding Pharmacokinetics, Detoxication, and Consequences—Cyp1Knockout Mouse Lines as a Paradigm

Effect of Type I Compounds on P-Hydroxylation of Aniline in Vitro

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