Mutagenic activation of aflatoxin B1 by P-450 HFLa in human fetal livers

Kitada, Munehiro; Taneda, M; Ohi, Hiroshi; Komori, Masaharu; Itahashi, Koshiro; Nagao, Minako; Kamataki, Tetsuya

doi:10.1016/0165-7992(89)90068-7

Cited by 32 publications

(14 citation statements)

References 18 publications

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“…An increase in placental CYP3A7 could divert the substrate flow to 16-ahydroxylated DHEA-s, a steroid that has no affect on progesterone synthesis ( 17). Finally, an important but as yet unexplored possibility is that, because some CYP3A forms can both activate and inactivate carcinogens (63)(64)(65)(66)(67), the change in the amount of CYP3A7 expressed in the reproductive system throughout pregnancy (if this enzyme carries out similar reactions) may play an important role in fetal toxicology during the critical periods in fetal development.…”

Section: Discussionmentioning

confidence: 99%

Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta.

Schuetz¹,

Kauma²,

Guzelian³

1993

J. Clin. Invest.

104

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Placenta and endometrium carry out steroidogenic biotransformation reactions such as 6-ft-hydroxylation of cortisol, a reaction characteristic of the dominant family of cytochromes P450 in human liver, CYP3A. To investigate the possible role in these extrahepatic tissues of the CYP3A microsomal hemoproteins, we analyzed placental and endometrial microsomes on Western blots developed with an anti-human CYP3A antibody. We found an immunoreactive 51,500 D protein that migrated between CYP3A3 (HLp) and CYP3A5 (HLp2) identical with CYP3A7 (HFLa). CYP3A7, a form found prominently in human fetal liver microsomes, was first isolated as a liver 16-adehydroepiandrosterone-sulfate hydroxylase. Northern blot analysis of total RNA isolated from placenta or from endometrium demonstrated a single band that cross-hybridized with a CYP3A7 cDNA. Amplification of the same RNA samples with the use of primers specific for CYP3A7, produced a 552-bp segment that had the predicted size and the same DNA sequence as does liver CYP3A7 cDNA. Hybridizable endometrial CYP3A7 mRNA was detected more frequently (six of seven samples) and in higher amounts (-12-fold higher) in pregnant compared with nonpregnant women (4 of 12 samples). In addition, during the secretory phase of the menstrual cycle CYP3A7 expression was sixfold higher than in the one sample from the proliferative phase that had detectable CYP3A7 mRNA. Moreover, the amounts of placental and endometrial CYP3A7 mRNA and protein increased substantially from the first to the second trimester of pregnancy. We conclude that placenta and endometrium express the same P450 as is found in fetal liver. These tissues represent a previously unrecognized and quantitatively important site for 6-ft-hydroxylation and 16-a-hydroxylation of specific steroid precursors, possibly for protection of the fetus from the toxic effects of endogenous steroids and foreign substrates. (J. Clin. Invest. 1993.

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Section: Discussionmentioning

confidence: 99%

Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta.

Schuetz¹,

Kauma²,

Guzelian³

1993

J. Clin. Invest.

104

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“…CYP3A is the most abundant form of CYP expressed in the human liver (Shimada et al, 1994) and is responsible for the metabolism of more than 50% of clinically used drugs, such as nifedipine, cyclosporine and midazolam (Rendic, 2002). This subfamily can also activate pro-carcinogens, including aflatoxin B 1 , to generate carcinogens (Kitada et al, 1989;Shimada & Guengerich, 1989).…”

Section: Introductionmentioning

confidence: 98%

Ethnic differences between Japanese and Caucasians in the expression levels of mRNAs for CYP3A4, CYP3A5 and CYP3A7: lack of co-regulation of the expression of CYP3A in Japanese livers

et al. 2005

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Using a newly developed real-time reverse transcriptase-polymerase chain reaction method, mRNAs were quantitated for CYP3A4, CYP3A5 and CYP3A7 in adult livers from 24 Japanese and 24 Caucasian subjects to elucidate the potential ethnic differences in the expression levels of human cytochrome P450 (CYP) 3As. The expression level of CYP3A4 mRNA in Japanese livers (n = 24) was approximately three times higher than that in Caucasian livers (n = 24, p < 0.001). The mean level of CYP3A5 mRNA was approximately twice higher in Japanese (n = 9) than in Caucasians (n = 5) heterozygous for the CYP3A5 *1 allele (p = 0.057). The CYP3A7 mRNA level was twice higher in Japanese (n = 24) than in Caucasians (n = 22) carrying the CYP3A7 *1A/ *1A genotype (p = 0.042). The level of CYP3A4 mRNA did not correlate with those of CYP3A5 (r = 0.044, n = 24) or CYP3A7 (r = 0.21, n = 24) mRNAs in Japanese livers in contrast to co-regulatory expression of CYP3A4, CYP3A5 and CYP3A7 in Caucasian livers. The results indicate that there are ethnic differences in the expression levels of adult liver CYP3A mRNAs between Japanese and Caucasians, and that the mechanism(s) regulating the hepatic CYP3A expression may be different between these ethnic groups.

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“…The mutagen-producing activities of purified preparations of cytochrome P-450 were examined in a reconstituted system containing cytochrome P-450, NADPH-cytochrome P-450 reductase, cytochrome b5 and other necessary components (Kitada et al 1989. The results are shown in Table 1.…”

Section: Mutagen-producing Capacity Of Human Fetal Liversmentioning

confidence: 99%

“…Both P-450HFLa and P-450HFLc showed high activities in the mutagen production from promutagens including aflatoxin B1. P-450HFLa, probably with P-450HFLc, was the major form of cytochrome P-450 involved in the activation of this mycotoxin (Kitada et al 1989). There was a close correlation between the content of P-450HFLa(c) in liver homogenates and the ability of the same homogenates to activate aflatoxin B1 (Fig.…”

Section: Properties Of P-450hflamentioning

confidence: 99%