pReVIously ClAssIfIed by IARC As “CARCInogenIC to humAns (gRoup 1)” And wAs deVeloped by sIx sepARAte woRkIng gRoups: phARmACeutICAls; bIologICAl Agents; ARsenIC, metAls, fIbRes, And dusts; RAdIAtIon; peRsonAl hAbIts And IndooR CombustIons; ChemICAl Agents And RelAted oCCupAtIons. thIs Volume 100f CoVeRs ChemICAl Agents And RelAted oCCupAtIons, speCIfICAlly 4-AmInobIphenyl, benzIdIne, dyes metAbolIzed to benzIdIne, 4,4’-methylenebIs(2-ChloRoAnIlIne), 2-nAphthylAmIne, oRtho-toluIdIne, AuRAmIne And AuRAmIne pRoduCtIon, mAgentA And mAgentA pRoduCtIon, benzo[A]pyRene, CoAl gAsIfICAtIon, oCCupAtIonAl exposuRes duRIng CoAl-tAR dIstIllAtIon, CoAl-tAR pItCh, Coke pRoduCtIon, untReAted oR mIldly tReAted mIneRAl oIls, shAle oIls, soot, As found In oCCupAtIonAl exposuRe of ChImney-sweeps, oCCupAtIonAl exposuRes duRIng AlumInIum pRoduCtIon, AflAtoxIns, benzene, bIs(ChloRomethyl)etheR And ChloRomethyl methyl etheR, 1,3-butAdIene, 2,3,7,8-tetRAChloRodIbenzo-pARA-dIoxIn, 2,3,4,7,8-pentAChloRodIbenzofuRAn, And 3,3’,4,4’,5-pentAChloRobIphenyl, ethylene oxIde, foRmAldehyde, sulfuR mustARd, VInyl ChloRIde, IsopRopyl AlCohol mAnufACtuRe by the stRong-ACId pRoCess, mIsts fRom stRong InoRgAnIC ACIds, oCCupAtIonAl exposuRes duRIng IRon And steel foundIng, oCCupAtIonAl exposuRe As A pAInteR, oCCupAtIonAl exposuRes In the RubbeR mAnufACtuRIng IndustRy. beCAuse the sCope of Volume 100 Is so bRoAd, Its monogRAphs ARe foCused on key InfoRmAtIon. eACh monogRAph pResents A desCRIptIon of A CARCInogenIC Agent And how people ARe exposed, CRItICAl oVeRVIews of the epIdemIologICAl studIes And AnImAl CAnCeR bIoAssAys, And A ConCIse ReVIew of the Agent’s toxICokInetICs, plAusIble meChAnIsms of CARCInogenesIs, And potentIAlly susCeptIble populAtIons, And lIfe-stAges. detAIls of the desIgn And Results of IndIVIduAl epIdemIologICAl studIes And AnImAl CAnCeR bIoAssAys ARe summARIzed In tAbles. shoRt tAbles thAt hIghlIght key Results ARe pRInted In Volume 100, And moRe extensIVe tAbles thAt InClude All studIes AppeAR on the monogRAphs pRogRAmme websIte (http://monogRAphs.IARC.fR). It Is hoped thAt thIs Volume, by CompIlIng the knowledge ACCumulAted thRough seVeRAl deCAdes of CAnCeR ReseARCh, wIll stImulAte CAnCeR pReVentIon ACtIVItIes woRldwIde, And wIll be A VAlued ResouRCe foR futuRe ReseARCh to IdentIfy otheR Agents suspeCted of CAusIng CAnCeR In humAns. D es ig n by A ude la d es m ot s

iArc monogrAphs on the evAluAtion oF cArcinogenic risks to humAns

Most nitroaromatic compounds are toxic and mutagenic for living organisms, but some microorganisms have developed oxidative or reductive pathways to degrade or transform these compounds. Reductive pathways are based either on the reduction of the aromatic ring by hydride additions or on the reduction of the nitro groups to hydroxylamino and/or amino derivatives. Bacterial nitroreductases are flavoenzymes that catalyze the NAD(P)H-dependent reduction of the nitro groups on nitroaromatic and nitroheterocyclic compounds. Nitroreductases have raised a great interest due to their potential applications in bioremediation, biocatalysis, and biomedicine, especially in prodrug activation for chemotherapeutic cancer treatments. Different bacterial nitroreductases have been purified and their biochemical and kinetic parameters have been determined. The crystal structure of some nitroreductases have also been solved. However, the physiological role(s) of these enzymes remains unclear. Nitroreductase genes are widely spread within bacterial genomes, but are also found in archaea and some eukaryotic species. Although studies on regulation of nitroreductase gene expression are scarce, it seems that nitroreductase genes may be controlled by the MarRA and SoxRS regulatory systems that are involved in responses to several antibiotics and environmental chemical hazards and to specific oxidative stress conditions. This review covers the microbial distribution, types, biochemical properties, structure and regulation of the bacterial nitroreductases. The possible physiological functions and the biotechnological applications of these enzymes are also discussed.

Reduction of polynitroaromatic compounds: the bacterial nitroreductases.

Drug-Metabolizing Ability of Molybdenum Hydroxylases

Biotransformation in Fishes

Mammalian aldehyde oxidases are a small group of proteins belonging to the larger family of molybdo-flavoenzymes along with xanthine oxidoreductase and other bacterial enzymes. The two general types of reactions catalyzed by aldehyde oxidases are the hydroxylation of heterocycles and the oxidation of aldehydes into the corresponding carboxylic acids. Different animal species are characterized by a different complement of aldehyde oxidase genes. Humans contain a single active gene, while marsupials and rodents are characterized by four such genes clustering at a short distance on the same chromosome. At present, little is known about the physiological relevance of aldehyde oxidases in humans and other mammals, although these enzymes are known to play a role in the metabolism of drugs and compounds of toxicological importance in the liver. The present article provides an overview of the current knowledge of genetics, evolution, structure, enzymology, tissue distribution and regulation of mammalian aldehyde oxidases.

Mammalian aldehyde oxidases: genetics, evolution and biochemistry

We examined the effect of oral intake of pure glucosylceramide derived from konjac extract on skin barrier function evaluated by transepidermal water loss (TEWL) in hairless mice with sodium dodecyl sulfate (SDS)induced skin roughness. The difference of TEWL between SDS-treated site and untreated sites in the pure glucosylceramide-fed group was significantly lower than that in control group on day 14 of ingestion. We investigated interleukin-1α (IL-1α )p roduction in the hairless mouse skin, and it was significantly lower in the glucosylceramide-fed group than that of control animals. This reduced IL-1α production should contribute to improvement of skin barrier function. To investigate the effect of oral intake of glucosylceramide in human, we conducted a randomized double-blind placebo-controlle ds tudy including 100 healthy subjects whose TEWL in cheek was relatively high. As a result, cheek TEWL was significantly lower in the test product group as compared with the control group in weeks 8 and 12 of ingestion (p =0 .023 and p =0 .002 respectively).

/pdf/oral-intake-of-glucosylceramide-improves-relatively-higher-1gcsbt0wm0.pdf

Oral Intake of Glucosylceramide Improves Relatively Higher Level of Transepidermal Water Loss in Mice and Healthy Human Subjects

In this study, we investigated whether dietary glucosylceramide (GlcCer) and its metabolite sphingoid bases, sphingosine (SS), phytosphingosine (PS), sphingadienine (SD) and 4-hydroxysphingenine (4HS), influence cornified envelope (CE) formation. CE is formed during terminal differentiation of the epidermis through crosslinking of specific precursor proteins by transglutaminases (TGases), and is essential for the skin's barrier function. Oral administration of GlcCer (0.25 mg/day) for 14 consecutive days dramatically reduced transepidermal water loss, an indicator of the skin barrier condition, in hairless mice with barrier perturbation induced by single-dose ultraviolet B (UVB) irradiation. The GlcCer treatment also increased the level of TGase-1 mRNA in UVB-irradiated murine epidermis approximately 1.6-fold compared with the control. Further, all four sphingoid bases at 1 μM concentration enhanced CE formation of cultured normal human keratinocyte cells. Among them, SS, PS and SD, but not 4HS, stimulated production of involucrin, one of the CE major precursor proteins. SD increased the expression of TGase-1 mRNA, while SS increased the expression of TGase-3 mRNA. These results indicate that the skin barrier improvement induced by oral GlcCer treatment might be at least partly due to a reinforcement of CE formation in the epidermis mediated by sphingoid bases metabolically derived from GlcCer.

Dietary Glucosylceramide Enhances Cornified Envelope Formation via Transglutaminase Expression and Involucrin Production

Molybdenum hydroxylases, aldehyde oxidase and xanthine oxidoreductase, were shown to be involved in the nitroreduction of 2-nitrofluorene (NF), 1-nitropyrene, and 4-nitrobiphenyl, environmental pollutants, in the skin of various mammalian species. NF was reduced to 2-aminofluorene by hamster skin cytosol in the presence of 2-hydroxypyrimidine, 4-hydroxypyrimidine, N(1)-methylnicotinamide, or benzaldehyde, but not hypoxanthine or xanthine. Inhibitors of aldehyde oxidase markedly inhibited these nitroreductase activities, but oxypurinol, an inhibitor of xanthine oxidoreductase, had little effect. In DEAE column chromatography of hamster skin cytosol, the major fraction exhibiting nitroreductase activity also showed aldehyde oxidase activity. 2-Hydroxypyrimidine-linked nitroreductase activities of skin cytosol from rabbits and guinea pigs were also inhibited by an inhibitor of aldehyde oxidase. In contrast, nitroreductase activities of skin cytosols of rats and mice were markedly inhibited by oxypurinol. When aldehyde oxidase activity was estimated in skin cytosol of various mammals using benzaldehyde oxidase activity as a marker, considerable variability of the activity was found. The highest activity was observed with hamsters, and the lowest activity with rats. On the other hand, the highest xanthine oxidoreductase activity was observed with rats, and the lowest activity with rabbits. These skin cytosols of various mammals also exhibited significant 2-hydroxypyrimidine-linked nitroreductase activities toward 1-nitropyrene and 4-nitrobiphenyl catalyzed by aldehyde oxidase and xanthine oxidoreductase. Thus, NF was mainly reduced by aldehyde oxidase and xanthine oxidoreductase in skins of animals. However, the contributions of these two molybdenum hydroxylases were considerably different among animal species.

https://dmd.aspetjournals.org/content/dmd/early/2005/06/02/dmd.105.005306.full.pdf

Involvement of molybdenum hydroxylases in reductive metabolism of nitro polycyclic aromatic hydrocarbons in mammalian skin

https://www.jstage.jst.go.jp/article/dmpk/24/2/24_2_180/_pdf

Distribution in skin of ceramide after oral administration to rats.

The reductive metabolism of 2-nitrofluorene, a carcinogenic air pollutant, in rat skin microsomes and cytosol was investigated. 2-Nitrofluorene was reduced to the corresponding amine by the microsomes with NADPH and by the cytosol with 2-hydroxypyrimidine or 4-hydroxypyrimidine under anaerobic conditions. The cytosolic activity was much higher than that of skin microsomes. The 2- or 4-hydroxypyrimidine-linked nitroreductase activity was inhibited by oxypurinol and (+/-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one (BOF-4272), inhibitors of xanthine oxidase, but not by menadione, chlorpromazine and isovanillin, inhibitors of aldehyde oxidase. When skin cytosol was applied to a DEAE-cellulose column, the fractions containing xanthine oxidase exhibited a marked 2-hydroxypyrimidine-linked nitroreductase activity. In contrast, the aldehyde oxidase fraction showed little activity. Nitroreductase fractions obtained by ion exchange chromatography showed a band in Western blotting analysis using anti-rat xanthine oxidase. Moreover, the xanthine oxidase fraction exhibited a significant nitroreductase activity in the presence of 2-hydroxypyrimidine, 4-hydroxypyrimidine or hypoxanthine, and these activities were inhibited by inhibitors of xanthine oxidase. These results indicated that reduction of 2-nitrofluorene in the skin was mainly catalyzed by xanthine oxidase.

Osamu Ueda

Papers

Oral Intake of Glucosylceramide Improves Relatively Higher Level of Transepidermal Water Loss in Mice and Healthy Human Subjects

Dietary Glucosylceramide Enhances Cornified Envelope Formation via Transglutaminase Expression and Involucrin Production

Involvement of molybdenum hydroxylases in reductive metabolism of nitro polycyclic aromatic hydrocarbons in mammalian skin

Distribution in skin of ceramide after oral administration to rats.

Xanthine oxidase-catalyzed metabolism of 2-nitrofluorene, a carcinogenic air pollutant, in rat skin.