Bioactivation of aflatoxin B1 by human liver microsomes: Role of cytochrome P450 IIIA enzymes

Ramsdell, Howard S.; Parkinson, Andrew; Eddy, A C; Eaton, David L.

doi:10.1016/0041-008x(91)90090-2

Cited by 75 publications

(37 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, in vitro studies using primate and human liver microsomes have demonstrated that AFQ 1 is a major AFB 1 metabolite, with AFM 1, the hydroxylated metabolite constituting less than 10% of the total metabolized AFB 1 [22][23]. Accordingly, in a study carried out in China, the levels of urinary AFQ 1 were 60 fold higher than those of AFM 1 .…”

Section: Introductionmentioning

confidence: 99%

A direct assessment of mycotoxin biomarkers in human urine samples by liquid chromatography tandem mass spectrometry

Ediage

Mavungu

Song

et al. 2012

Analytica Chimica Acta

121

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

A direct assessment of mycotoxin biomarkers in human urine samples by liquid chromatography tandem mass spectrometry

Ediage

Mavungu

Song

et al. 2012

Analytica Chimica Acta

121

View full text Add to dashboard Cite

“…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%

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

View full text Add to dashboard Cite

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...

show abstract

“…In humans (Homo sapiens), multiple hepatic P450 enzymes can activate AFB1, but P450 1A2 and 3A4 are the primary producers of AFBO [4,43,[63][64][65][66][67]. Human P450 3A4 is active at high AFB1 concentrations, while P450 1A2 has high affinity at low biologically-relevant concentrations [64,66]. Overall, human P450 enzymes produce far less AFBO than rodents, even at high concentrations of AFB1 (1/4 that of rats, 1/8 that of mice) [48].…”

Section: Etiology Of Aflatoxicosismentioning

confidence: 99%

Aflatoxicosis: Lessons from Toxicity and Responses to Aflatoxin B1 in Poultry

2015

View full text Add to dashboard Cite

This review is a comprehensive introduction to the effects of poultry exposure to the toxic and carcinogenic mycotoxin aflatoxin B1 (AFB1). The relationship between AFB1 sensitivity and metabolism, major direct and indirect effects of AFB1, recent studies of gene expression and transcriptome responses to exposure, and mitigation strategies to reduce toxicity are discussed. Exposure to AFB1 primarily occurs by consumption of contaminated corn, grain or other feed components. Low levels of residual AFB1 in poultry feeds can cause reduction in growth, feed conversion, egg production, and compromised immune functions, resulting in significant economic costs to producers. Thus, AFB1 acts as a "force multiplier" synergizing the adverse effects of microbial pathogens and other agents, and factors detrimental to poultry health. Domestic turkeys (Meleagris gallopavo) are one of the most sensitive animals known to AFB1 due, in large part, to a combination of efficient hepatic bioactivation by cytochromes P450 1A5 and 3A37, and deficient hepatic glutathione-S-transferase (GST)-mediated detoxification. Because of their sensitivity, turkeys are a good model to investigate chemopreventive treatments and feed additives for their ability to reduce AFB1 toxicity. Transcriptome analysis (RNA-seq) of turkey poults (liver and spleen) has identified AFB1-induced gene expression changes in pathways of apoptosis, carcinogenesis, lipid regulation, antimicrobial activity, cytotoxicity and antigen presentation. Current research focuses on further identifying the molecular mechanisms OPEN ACCESSAgriculture 2015, 5 743 underlying AFB1 toxicity with the goal of reducing aflatoxicosis and improving poultry health.

show abstract

Bioactivation of aflatoxin B1 by human liver microsomes: Role of cytochrome P450 IIIA enzymes

Cited by 75 publications

References 33 publications

A direct assessment of mycotoxin biomarkers in human urine samples by liquid chromatography tandem mass spectrometry

A direct assessment of mycotoxin biomarkers in human urine samples by liquid chromatography tandem mass spectrometry

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

Aflatoxicosis: Lessons from Toxicity and Responses to Aflatoxin B1 in Poultry

Contact Info

Product

Resources

About

Bioactivation of aflatoxin B1 by human liver microsomes: Role of cytochrome P450 IIIA enzymes

Cited by 75 publications

References 33 publications

A direct assessment of mycotoxin biomarkers in human urine samples by liquid chromatography tandem mass spectrometry

A direct assessment of mycotoxin biomarkers in human urine samples by liquid chromatography tandem mass spectrometry

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

Aflatoxicosis: Lessons from Toxicity and Responses to Aflatoxin B1 in Poultry

Contact Info

Product

Resources

About

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