The Kinetics of Aflatoxin B1Oxidation by Human cDNA-Expressed and Human Liver Microsomal Cytochromes P450 1A2 and 3A4

Gallagher, Evan P.; Kunze, Kent L.; Stapleton, Patricia L.; Eaton, David L.

doi:10.1006/taap.1996.0326

Cited by 225 publications

(161 citation statements)

References 4 publications

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“…32,33 AFQ 1 is produced from AFB 1 in the liver by the CYP3A4 pathway, while AFM 1 is exclusively produced by CYP1A2. Affinity of CYP3A4 to AFB 1 varies with AFB 1 concentration: 13,32 at low concentrations (e.g., less than 1 mM in vitro) CYP3A4 has very low affinity to AFB 1 . Thus, at the concentrations of AFB 1 in human liver following ingestion of AFB 1 -contaminated diets, CYP1A2 is thought to be the single most important CYP enzyme metabolizing AFB 1 .…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, CYP3A4 is known as one of the major CYP enzymes in the liver, 13,[17][18][19][20] and in vitro studies using primate and human liver microsomes have demonstrated that AFQ 1 is a major AFB 1 metabolite.…”

Section: 3mentioning

confidence: 99%

“…12 It has been suggested that CYP1A2, catalyzing the formation of AFM 1 from AFB 1 , is the predominant enzyme responsible for the in vivo AFB 1 activation in liver at the concentrations encountered in human diet. 13 AFM 1 is one of the major metabolites found in the urine of subjects exposed to AFB 1 in vivo, and its level correlates with the presence of AFB 1 -serum albumin adducts, an established biomarker for dietary exposure to aflatoxins. 2,[14][15][16] However, quantitative data on AFM 1 excretion into feces are limited.…”

Section: Guanine; Hepatitis B Virusmentioning

confidence: 99%

“…2,[14][15][16] However, quantitative data on AFM 1 excretion into feces are limited. On the other hand, CYP3A4 is known as one of the major CYP enzymes in the liver, 13,[17][18][19][20] and in vitro studies using primate and human liver microsomes have demonstrated that AFQ 1 is a major AFB 1 metabolite. 21,22 Excretion of AFQ 1 , especially fecal excretion in humans, has not been quantitatively or qualitatively characterized.…”

Section: Guanine; Hepatitis B Virusmentioning

confidence: 99%

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Fecal and urinary excretion of aflatoxin B₁ metabolites (AFQ₁, AFM₁ and AFB‐N⁷‐guanine) in young Chinese males

Mykkänen

Zhu

Salminen

et al. 2005

Intl Journal of Cancer

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Our study was designed to assess the fecal and urinary excretion of 3 aflatoxin B 1 (AFB 1 ) metabolites, aflatoxins M 1 (AFM 1 ) and Q 1 (AFQ 1 ) and aflatoxin B 1 -N 7 -guanine (AFB-N 7 -guanine) that are produced by the predominant forms of cytochrome P450 enzymes responsible for the biotransformation of AFB 1 . Fecal and urinary AFM 1 , AFQ 1 and urinary AFB-N 7 -guanine were assessed in 83 young Chinese males selected from a larger population (n = 300) based on detectable urinary AFM 1 . The concentration of fecal AFQ 1 (median 137 ng/g fresh weight, IQR 9.1 to 450) was approximately 60 times higher than that of AFM 1 (2.3 ng/g, IQR 0.0 to 7.3). In urine, the median AFQ 1 was 10.4 ng/ml (IQR 3.4 to 23.3), and the median AFM 1 and AFB-N 7 -guanine 0.04 ng/ml (IQR 0.01 to 0.33) and 0.38 ng/ml (IQR 0.0 to 2.15), respectively. A subgroup (n = 14) with hepatitis B virus (HBV) infection had significantly higher fecal concentrations of AFQ 1 ( p = 0.043) and AFM 1 ( p = 0.001) than those who were hepatitis B-virus antigen (HBsAg) negative, and the respective differences in urinary AFQ 1 and AFM 1 concentrations approached statistical significance ( p = 0.054, p = 0.138). Our study demonstrates that AFQ 1 is excreted in urine and feces at higher levels than AFM 1 , and feces are an important route of excretion of these AFB 1 metabolites. AFQ 1 should be further assessed for its predictive value as a marker for exposure and risk of dietary aflatoxins. The most serious health effect of dietary exposure to aflatoxins is hepatocellular carcinoma. The etiology of this disease also involves chronic infection with hepatitis B and C viruses (HBV and HCV), and a significant synergistic interaction between aflatoxin exposure and hepatitis B virus has been reported. 2,3After oral uptake AFB 1 is efficiently absorbed and metabolized prior to excretion by fecal and urinary routes (Fig. 1). Absorbed AFB 1 and its metabolites are excreted in urine, while elimination to feces is a route for both the unabsorbed AFB 1 and biliary excretion of metabolites formed from the absorbed toxin. Animal studies have shown that under normal conditions 50% of the orally administered dose of AFB 1 is quickly absorbed from the duodenal region of the small intestine 4 and enters the liver through the hepatic portal blood supply.5 AFB 1 is concentrated in the liver and to a lesser extent in kidney, 6 and it is also found in the mesenteric venous blood as free AFB 1 or its water-soluble metabolites.Members of the cytochrome P450 (CYP) enzyme family, CYP1A2, CYP3A4 and CYP2A6 have been shown to be responsible for the metabolism of the absorbed aflatoxins 7,8 (Fig. 1). These enzymes convert AFB 1 to its carcinogenic form, AFB-8,9-epoxide, which is covalently bound to DNA 9 and serum albumin, 10 forming aflatoxin B 1 -N 7 -guanine (AFB-N 7 -guanine) and lysine adducts, respectively. These enzymes also oxidize AFB 1 to various other derivatives, including aflatoxin M 1 (AFM 1 ), aflatoxin Q 1 (AFQ 1 ), aflatoxin P 1 as well as a reduced aflatoxin species...

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Section: Discussionmentioning

confidence: 99%

Section: 3mentioning

confidence: 99%

Section: Guanine; Hepatitis B Virusmentioning

confidence: 99%

Section: Guanine; Hepatitis B Virusmentioning

confidence: 99%

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Fecal and urinary excretion of aflatoxin B₁ metabolites (AFQ₁, AFM₁ and AFB‐N⁷‐guanine) in young Chinese males

Mykkänen

Zhu

Salminen

et al. 2005

Intl Journal of Cancer

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“…In contrast, CYP2A6 is not active for these substrates. These activities had been known to be catalyzed by CYP1A2 (Gallagher et al, 1996;Hammons et al, 1997). In the present study, we investigated whether CYP2A13 has the ability to metabolize the compounds that are representative substrates of CYP1A2.…”

mentioning

confidence: 99%

CYP2A13 Metabolizes the Substrates of Human CYP1A2, Phenacetin, and Theophylline

Fukami¹,

Nakajima²,

Sakai³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Human cytochrome CYP2A13 shows overlapping substrate specificity with CYP2A6, catalyzing the metabolism of coumarin, nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Recently, it was found that CYP2A13 could catalyze the metabolic activations of 4-aminobiphenyl and aflatoxin B 1 , which are known to be catalyzed by human CYP1A2. In the present study, we investigated the substrate specificity of CYP2A13. It was shown that CYP2A13 could catalyze ethoxyresorufin O-deethylation, methoxyresorufin O-demethylation, and phenacetin O-deethylation, which are used as marker activities for human CYP1A2. Although the intrinsic clearances (V max /K m ) of the two former reactions by CYP2A13 were much lower than that of CYP1A2, the value of the last reaction by CYP2A13 was 2-fold higher than that of CYP1A2.Of particular interest was that CYP2A13 has higher affinity toward phenacetin than CYP1A2. In contrast, CYP2A6 hardly catalyzed these reactions, although the amino acid identity with CYP2A13 is as high as 93.5%. Furthermore, we found that CYP2A13 can catalyze theophylline 8-hydroxylation and 3-demethylation, which are known to be mainly catalyzed by human CYP1A2, although the intrinsic clearances were approximately one-tenth that of CYP1A2. CYP2A13 would not contribute to the systemic clearance of these drugs because CYP2A13 is hardly expressed in human liver. However, it may play a role in metabolism in local tissues such as lung or trachea. In conclusion, the results of the present study could extend our understanding of the substrate specificity of CYP2A13.

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Biotransformation

Eaton,

Cui

2023

Patty's Toxicology

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Biotransformation—or the process by which the body changes the chemical structure of an exogenous chemical—is an essential component in the development of toxic responses to chemicals found in the workplace and general environment. There are hundreds of biotransformation enzymes that act on chemicals to change their chemical structure within the body. Many of these biotransformation enzymes (often called “drug‐metabolizing enzymes,” or DMEs) also play essential roles in the formation and elimination of important endogenous biomolecules, such as steroid hormones, neurotransmitters, and other signaling molecules. However, a subset of these enzymes appears to exist primarily for the purposes of detoxifying exogenous chemicals (xenobiotics). Because most of these enzymes are not essential to life, genetic polymorphisms are common and can impart large differences in susceptibility to certain chemicals found in our workplace, diet, or general environment. This chapter discusses the large multi‐gene families of enzymes that are involved in oxidation, reduction, hydrolysis, and conjugation of xenobiotics. Although the purpose of biotransformation processes is to facilitate both the detoxication and elimination of xenobiotics from the body, it often happens that short‐lived, reactive intermediates are formed in the process, and these may be more toxic than the parent molecule. Understanding the pathways of biotransformation, and how these pathways can contribute to both acute and chronic toxic effects of xenobiotics, is an important part of the field of toxicology as it pertains to workplace and environmental exposures to toxic substances.

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The Kinetics of Aflatoxin B1Oxidation by Human cDNA-Expressed and Human Liver Microsomal Cytochromes P450 1A2 and 3A4

Cited by 225 publications

References 4 publications

Fecal and urinary excretion of aflatoxin B₁ metabolites (AFQ₁, AFM₁ and AFB‐N⁷‐guanine) in young Chinese males

Fecal and urinary excretion of aflatoxin B₁ metabolites (AFQ₁, AFM₁ and AFB‐N⁷‐guanine) in young Chinese males

CYP2A13 Metabolizes the Substrates of Human CYP1A2, Phenacetin, and Theophylline

Biotransformation

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The Kinetics of Aflatoxin B1Oxidation by Human cDNA-Expressed and Human Liver Microsomal Cytochromes P450 1A2 and 3A4

Cited by 225 publications

References 4 publications

Fecal and urinary excretion of aflatoxin B1 metabolites (AFQ1, AFM1 and AFB‐N7‐guanine) in young Chinese males

Fecal and urinary excretion of aflatoxin B1 metabolites (AFQ1, AFM1 and AFB‐N7‐guanine) in young Chinese males

CYP2A13 Metabolizes the Substrates of Human CYP1A2, Phenacetin, and Theophylline

Biotransformation

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Product

Resources

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Fecal and urinary excretion of aflatoxin B₁ metabolites (AFQ₁, AFM₁ and AFB‐N⁷‐guanine) in young Chinese males

Fecal and urinary excretion of aflatoxin B₁ metabolites (AFQ₁, AFM₁ and AFB‐N⁷‐guanine) in young Chinese males