Effect of Arsenite on Induction of CYP1A, CYP2B, and CYP3A in Primary Cultures of Rat Hepatocytes

Jacobs, Judith M.; Nichols, Claude E.; Andrew, Angeline S.; Marek, Doreen; Wood, Sheryl G.; Sinclair, Peter R.; Wrighton, Steven; Kostrubsky, Vsevolod E.; Sinclair, Jacqueline F.

doi:10.1006/taap.1999.8659

Cited by 51 publications

(51 citation statements)

References 27 publications

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“…Arsenite has been previously shown to reduce the levels of hepatic P450s of the CYP1A (Falkner et al, 1993;Jacobs et al, 1999;Vakharia et al, 2001), CYP2B (Jacobs et al, 1999), and CYP3A families (Jacobs et al, 1999). The results reported here indicate that the effect of arsenite on the expression of cytochromes P450 is retained in a transformed, immortalized cell line derived from a human breast carcinoma.…”

Section: Fig 8 Effects Of Bap and Naaso 2 On The Levels Of Cpr And supporting

confidence: 58%

“…The induction of HO-1 by arsenite and the subsequent reduction in the availability of heme as the prosthetic group for P450s may explain the reduced P450 activities in T-47D cells, hepatocyte cultures, and in vivo. However, recent studies by Jacobs et al (1999) suggest that induction of HO-1 may not completely explain the effect of arsenite on P450 expression. HO-1 is also induced by heme in hepatocyte cultures, but treatment with heme did not result in reduced P450 levels, whereas cotreatment of hepatocyte cultures with arsenite and heme diminished levels of CYP2B1/2 (Jacobs et al, 1999).…”

Section: Fig 8 Effects Of Bap and Naaso 2 On The Levels Of Cpr And mentioning

confidence: 98%

“…Because the induction of HO-1 has been observed in response to arsenite exposure in vivo (Falkner et al, 1993) and in vitro (Jacobs et al, 1999), concomitant with the reduction of P450 activities, we investigated whether HO-1 mRNA was induced under the conditions of the experiment in Fig. 5, in which rates of CYP1A1-and CYP1B1-catalyzed E 2 metabolism were diminished by added NaAsO 2 .…”

Section: Spink Et Almentioning

confidence: 99%

“…There are several potential points, including transcription, translation, and incorporation of the heme prosthetic group, at which other chemicals, including environmental cocontaminants, could potentially modulate expression and catalytic activity of CYP1A1, CYP1B1, and other P450s. In several recent studies, an effect of arsenite on expression of cytochromes P450 in hepatocyte cultures was reported (Jacobs et al, 1999;Vakharia et al, 2001), although the mechanism responsible for this effect has not been determined.…”

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confidence: 99%

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Induction of CYP1A1 and CYP1B1 in T-47D Human Breast Cancer Cells by Benzo[a]pyrene Is Diminished by Arsenite

Spink

Katz²,

Hussain³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Polycyclic aromatic hydrocarbons (PAHs) and metals are often environmental cocontaminants, yet there have been relatively few studies of combined effects of PAHs and metals on cytochrome P450 (P450)-catalyzed metabolism. We examined the effects of NaAsO 2 in combination with benzo[a]pyrene (BAP) on CYP1A1 and CYP1B1 in T-47D human breast cancer cells by using estrogen metabolism as a probe of their activities. Exposure to BAP caused elevated rates of the 2-and 4-hydroxylation pathways of estrogen metabolism, indicating induction of both CYP1A1, an estradiol 2-hydroxylase, and CYP1B1, an estradiol 4-hydroxylase. BAP-induced metabolism peaked 9 to 16 h after exposure and returned to near-basal levels by 48 h. Concentration-response studies showed maximal induction of the 2-and 4-hydroxylation pathways at 3 M BAP; higher levels caused reduced rates of metabolism due to inhibition of CYP1A1 and CYP1B1. NaAsO 2 caused pronounced decreases in the induction of CYP1A1 and CYP1B1 by 3 M BAP because cotreatment with 10 M NaAsO 2 inhibited the rates of the 2-and 4-hydroxylation pathways by 86 and 92%, respectively. Western immunoblots showed diminished levels of BAP-induced CYP1A1 by coexposure to NaAsO 2 . The levels of the CYP1A1 and CYP1B1 mRNAs induced by BAP were not significantly affected by coexposure to NaAsO 2 ; however, heme oxygenase 1 mRNA levels were markedly induced by coexposure to BAP and NaAsO 2 . These results indicate a post-transcriptional inhibitory effect of arsenite on the expression of CYP1A1 and CYP1B1 in T-47D cells, possibly resulting from reduced heme availability.Among the environmental contaminants of most concern due to their toxicity, including carcinogenicity, are heavy metals, such as arsenic, lead, and mercury, and polycyclic aromatic hydrocarbons (PAHs 1 ) typified by benzo[a]pyrene (BAP). PAHs and heavy metals are often cocontaminants in the environment, yet there have been relatively few studies of the combined toxic and particularly the carcinogenic effects elicited by PAHs and heavy metals. The carcinogenicity of BAP and other PAHs is a consequence of their metabolic activation catalyzed by cytochromes P450 (P450) and epoxide hydrolase (Wood et al., 1976;Kapitulnik et al., 1978). Covalent adducts formed by the reaction of PAH diol epoxide metabolites with guanine in mutational hotspots of critical genes such as that of the p53 tumor suppressor (Denissenko et al., 1996), if not efficiently repaired, may initiate tumorigenesis.Several members of the P450 superfamily in conjunction with epoxide hydrolase have been shown to catalyze the metabolism of BAP to carcinogenic intermediates. In extrahepatic tissues, CYP1A1 and CYP1B1 are thought to be the most important enzymes in catalyzing the formation of mutagenic intermediates from BAP and a number of other PAHs, including several that are potent mammary gland carcinogens in rodents. CYP1B1 appears to be more active than CYP1A1 in the conversion of a number of PAHs to genotoxic intermediates (Shimada et al., 1996). In the presence...

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Section: Fig 8 Effects Of Bap and Naaso 2 On The Levels Of Cpr And supporting

confidence: 58%

Section: Fig 8 Effects Of Bap and Naaso 2 On The Levels Of Cpr And mentioning

confidence: 98%

Section: Spink Et Almentioning

confidence: 99%

mentioning

confidence: 99%

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Induction of CYP1A1 and CYP1B1 in T-47D Human Breast Cancer Cells by Benzo[a]pyrene Is Diminished by Arsenite

Spink

Katz²,

Hussain³

et al. 2002

Drug Metab Dispos

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“…P450-catalyzed metabolism is recognized as a source of free radicals, notably when futile catalytic cycles occur with poorly metabolized substrates such as PCBs and TCDD (305,306). Coincident with the induction of HO-1 by arsenite is the reduction of the expression of P450s of several gene families (307,308). Although heme availability for the prosthetic group of P450 is undoubtedly at least partially responsible for the effect, there appear to be several pathways in which oxidant signals result in an effect on P450 expression.…”

Section: Heavy Metal-organic Toxicant Interactionsmentioning

confidence: 99%

Understanding the human health effects of chemical mixtures.

Carpenter

Arcaro

Spink

2002

Environ Health Perspect

329

198

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Most research on the effects of chemicals on biologic systems is conducted on one chemical at a time. However, in the real world people are exposed to mixtures, not single chemicals. Although various substances may have totally independent actions, in many cases two substances may act at the same site in ways that can be either additive or nonadditive. Many even more complex interactions may occur if two chemicals act at different but related targets. In the extreme case there may be synergistic effects, in which case the effects of two substances together are greater than the sum of either effect alone. In reality, most persons are exposed to many chemicals, not just one or two, and therefore the effects of a chemical mixture are extremely complex and may differ for each mixture depending on the chemical composition. This complexity is a major reason why mixtures have not been well studied. In this review we attempt to illustrate some of the principles and approaches that can be used to study effects of mixtures. By the nature of the state of the science, this discussion is more a presentation of what we do not know than of what we do know about mixtures. We approach the study of mixtures at three levels, using specific examples. First, we discuss several human diseases in relation to a variety of environmental agents believed to influence the development and progression of the disease. We present results of selected cellular and animal studies in which simple mixtures have been investigated. Finally, we discuss some of the effects of mixtures at a molecular level.

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Modulation of AHR Function by Heavy Metals and Disease States

Anwar‐Mohammed

El‐Kadi

2011

The AH Receptor in Biology and Toxicology

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Effect of Arsenite on Induction of CYP1A, CYP2B, and CYP3A in Primary Cultures of Rat Hepatocytes

Cited by 51 publications

References 27 publications

Induction of CYP1A1 and CYP1B1 in T-47D Human Breast Cancer Cells by Benzo[a]pyrene Is Diminished by Arsenite

Induction of CYP1A1 and CYP1B1 in T-47D Human Breast Cancer Cells by Benzo[a]pyrene Is Diminished by Arsenite

Understanding the human health effects of chemical mixtures.

Modulation of AHR Function by Heavy Metals and Disease States

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