Lactoperoxidase-Catalyzed Activation of Carcinogenic Aromatic and Heterocyclic Amines

Gorlewska-Roberts, K.; Teitel, Candee H.; Lay, Jackson O.; Roberts, Dean W.; Kadlubar, Fred F.

doi:10.1021/tx049787n

Cited by 58 publications

(41 citation statements)

References 24 publications

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“…Aromatic amines are a major class of tobacco carcinogens, which include 2-naphthylamine and 4-aminobiphenyl, two compounds known to cause cancer in both animals and humans (39,40). Epidemiologic studies have provided consistent evidence for a causal relationship between aromatic amines and urinary bladder cancer (41)(42)(43), and experimental studies have shown that aromatic amines are mammary carcinogens in rodents and humans (44)(45)(46)(47). The metabolism of aromatic amines includes the activation and detoxification by metabolic enzymes, such as cytochrome P450s and N-acetyltransferase, and the Nacetylation process by NAT2 is an important detoxification step for aromatic amines (48).…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoking, N-Acetyltransferase 2 Genotypes, and Breast Cancer Risk: Pooled Analysis and Meta-analysis

Ambrosone

Kropp

Yang

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

109

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Approximately 10 years ago, it was noted that smoking increased risk of breast cancer among women with Nacetyltransferase 2 (NAT2) slow acetylation genotypes. This report was followed by a number of studies to address this question. We pooled data from 10 existing studies and also conducted a meta-analysis of 13 studies published from 1996 to October 2006 that were conducted among women, were published in English, and had adequate information on smoking and NAT2 genotyping. Raw data were requested from authors. Unconditional logistic regression was done for pooled analysis, and random effect models was done for metaanalysis. Study heterogeneity was assessed, and sensitivity tests were done when subgroups were excluded from the analysis. In the pooled analysis, there was a significant interaction between smoking, NAT2 genotype, and risk of breast cancer [pack-years (continuous variable, P interaction = 0.03)], with higher pack-years significantly associated with an increased risk of breast cancer among women with NAT2 slow genotypes (pooled analysis relative risk, 1.49; 95% confidence interval, 1.08-2.04). These findings were supported by the meta-analysis including all studies; pack-years were significantly associated with risk among slow acetylators in a dose-dependent fashion (meta-analysis relative risk, 1.44; 95% confidence interval, 1.23-1.68 for z20 pack-years versus never smokers), but not among rapid acetylators. Similar relationships were noted for smoking status (ever, never) and duration of smoking. Our results show that cigarette smoking is associated with an increase in breast cancer risk among women with NAT2 slow acetylation genotypes. Because slow NAT2 genotypes are present in 50% to 60% of Caucasian populations, smoking is likely to play an important role in breast cancer etiology. (Cancer Epidemiol Biomarkers Prev 2008;17(1):15 -26)

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Section: Discussionmentioning

confidence: 99%

Cigarette Smoking, N-Acetyltransferase 2 Genotypes, and Breast Cancer Risk: Pooled Analysis and Meta-analysis

Ambrosone

Kropp

Yang

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

109

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“…Although lactoperoxidase (Gorlewska-Roberts et al, 2004), myeloperoxidase (Uetrecht et al, 1993), and thyroid peroxidase (Gupta et al, 1992) have been shown to bioactivate arylamines to reactive metabolites in vitro, none of these enzymes seems to be expressed in cultured human KCs (Vyas et al, 2006b). However, it is noteworthy that peroxidase inhibition reduces the bioactivation of dapsone in human KC cultures (Vyas et al, 2006b)-substantiating a role for peroxidases in cutaneous bioactivation.…”

Section: Evidence For the Expression Of Drug-metabolizing Enzymes In mentioning

confidence: 99%

Biotransformation of Drugs in Human Skin

Svensson

2008

Drug Metab Dispos

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ABSTRACT:Although it is the largest organ of the human body, skin is often not considered in discussions of drug metabolism. However, there is growing evidence that most common drug-metabolizing enzymes are expressed in the skin. Evidence for expression of cytochromes P450, flavin monooxygenases, glutathione-S-transferases, N-acetyltransferases, and sulfotransferases in human skin and skin cells are presented. Additional discussion is focused on the evidence of actual metabolism of drugs. Finally, the potential clinical implications of metabolism within the skin are discussed briefly.Representing the largest organ in the human body, skin provides an important barrier role in protecting the body from external chemicals and pathogens that would otherwise impair critical functions needed for survival. Comprised of a complex cellular network, skin is capable of many metabolic functions common to visceral organs, including the biotransformation of drugs that penetrate through its most external layer. In addition to being an important target for pharmacotherapy, delivery through the skin is increasingly used as an effective means of delivering drugs to the systemic circulation. It is also evident that biotransformation within the skin may be an essential step to manifesting cutaneous toxicity to certain drugs and chemicals. Hence, an understanding of the capacity and impact of drug biotransformation within skin is an important component in assessing pharmacotherapy directed to or through the cutaneous environment. In the present article, discussion will be limited to evidence for biotransformation of drugs generated specifically in human skin or skin cells. Although many investigations have probed the ability of skin from numerous species to metabolize a variety of environmental chemicals, the focus of the present review is on evidence for metabolism of therapeutic agents. The reader is referred to the recent review of Oesch et al. (2007) for a comparison of xenobiotic-metabolizing enzymes in the skin of various species. Overview of the Structure and Function of SkinExisting as a dynamic and flexible barrier, human skin serves a multifaceted role as the organ with the greatest exposure to the external environment. In addition to providing the primary means for tactile evaluation of the immediate surroundings, skin serves a critical role in thermoregulation of the body. The plethora of infectious diseases with cutaneous manifestations attests to the important sentinel role of skin in protecting the body from bacterial, fungal, and viral pathogens. Although this diversity of function is recognized, it is not surprising that skin is populated by numerous types of specialized cells (see Table 1) that enable dynamic interaction with the internal and external environment. Because studies assessing the role of skin in drug metabolism often use model cells, it is important to begin this review with a brief discussion of skin structure and function.Three identifiable layers comprise human skin: epidermis, dermis, and hypodermi...

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“…LPO and MPO) ellipticine can be oxidized to intermediates modifying key molecules such as DNA in this tissue. Hydrogen peroxide, required for peroxidase-mediated oxidations, comes from respiratory burst of neutrophils and is also supplied by xanthine oxidase 65,66 . The finding that ovine COX-1 and human COX-2 are capable of oxidative activation of ellipticine seems to have even greater significance.…”

Section: Oxidation Of Ellipticine By Peroxidases: Another Way To Metamentioning

confidence: 99%

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Stiborová¹,

Rupertová²,

Schmeiser³

et al. 2006

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Ellipticine is a potent antineoplastic agent exhibiting the multimodal mechanism of its action. This article reviews the mechanisms of predominant pharmacological and cytotoxic effects of ellipticine and shows the results of our laboratories indicating a novel mechanism of its action. The prevalent mechanisms of ellipticine antitumor, mutagenic and cytotoxic activities were suggested to be intercalation into DNA and inhibition of DNA topoisomerase II activity. We demonstrated a new mode of ellipticine action, formation of covalent DNA adducts mediated by its oxidation with cytochromes P450 (CYP) and peroxidases. The article reports the molecular mechanism of ellipticine oxidation by CYPs and identifies human and rat CYPs responsible for ellipticine metabolic activation and detoxication. It also presents a role of peroxidases (i.e. myeloperoxidase, cyclooxygenases, lactoperoxidase) in ellipticine oxidation leading to ellipticine-DNA adducts. The 9-hydroxy-and 7-hydroxyellipticine metabolites formed by CYPs and the major product of ellipticine oxidation by peroxidases, the dimer, in which the two ellipticine skeletons are connected via N 6 of the pyrrole ring of one ellipticine molecule and C9 in the second one, are the detoxication metabolites. On the contrary, 13-hydroxy-and 12-hydroxyellipticine, produced by ellipticine oxidation with CYPs, the latter one formed also spontaneously from another CYP-and peroxidase-mediated metabolite, ellipticine N 2 -oxide, are metabolites responsible for formation of two ellipticine-derived deoxyguanosine adducts in DNA. The results reviewed here allow us to propose species, two carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating two major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine.

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Lactoperoxidase-Catalyzed Activation of Carcinogenic Aromatic and Heterocyclic Amines

Cited by 58 publications

References 24 publications

Cigarette Smoking, N-Acetyltransferase 2 Genotypes, and Breast Cancer Risk: Pooled Analysis and Meta-analysis

Cigarette Smoking, N-Acetyltransferase 2 Genotypes, and Breast Cancer Risk: Pooled Analysis and Meta-analysis

Biotransformation of Drugs in Human Skin

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

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