Journal ArticleDOI
Role of cytochrome P450 1a1 and 1b1 in the metabolic activation of 7,12-dimethylbenz[a]anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation.
Heather E. Kleiner,Suryanarayana V. Vulimiri,Melissa J. Reed,and Ann Uberecken,John DiGiovanni +4 more
TLDR
The role of P450 1a1 and 1b1 in the metabolic activation of DMBA in mouse epidermis is demonstrated and provides a mechanistic explanation for the differential effects of naturally occurring furanocoumarins (and 7,8-BF) on polycyclic aromatic hydrocarbon skin carcinogenesis.Abstract:
The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or isopimpinellin (100-3200 nmol), 7,8-benzoflavone (7,8-BF, 5-40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which preferentially express P450 1b1 and P450 1a1, respectively, were co-incubated with 2 microM bergamottin, imperatorin, isopimpinellin, and 7,8-BF, and with DMBA (2 microM). Hepa-1 cells (P450 1a1) formed mainly anti-DMBADE-DNA adducts. In contrast, 10T1/2 cells (P450 1b1) formed mainly syn-DMBADE-DNA adducts. Bergamottin inhibited DMBA metabolism to DMBA-3,4-diol and blocked DNA adduct formation in Hepa-1 cells, but had little effect in 10T1/2 cells. In contrast, 7,8-BF completely blocked DMBA metabolism and DNA adduct formation in 10T1/2 cells, but had little effect in Hepa-1 cells. Imperatorin and isopimpinellin inhibited DMBA bioactivation in both cell lines. These results indicate that bergamottin is a more selective inhibitor of P450 1a1 and overall a less effective inhibitor of the metabolic activation of DMBA in mouse epidermis. In contrast, imperatorin, isopimpinellin, and especially 7,8-BF, which block metabolic activation of DMBA in mouse epidermis, appear more selective for P450 1b1. On the basis of our studies using 10T1/2 cells and Hepa-1 cells, it appears that P450 1a1 is primarily responsible for converting DMBA-3,4-diol to anti-DMBADE, whereas P450 1b1 is primarily responsible for converting DMBA-3,4-diol to syn-DMBADE. These data demonstrate the role of P450 1a1 and 1b1 in the metabolic activation of DMBA in mouse epidermis and provide a mechanistic explanation for the differential effects of naturally occurring furanocoumarins (and 7,8-BF) on polycyclic aromatic hydrocarbon skin carcinogenesis.read more
Citations
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Xenobiotic-metabolizing enzymes involved in activation and detoxification of carcinogenic polycyclic aromatic hydrocarbons
TL;DR: Inter-individual differences exist in levels of expression and catalytic activities of a variety of enzymes that activate and/or detoxify PAHs in various organs of humans and these phenomena are thought to be critical in understanding the basis of individual differences in response toPAHs.
Journal ArticleDOI
Herb-drug interactions: a literature review.
Zeping Hu,Xiaoxia Yang,Paul C. Ho,Sui Yung Chan,Paul Wan Sia Heng,Eli Chan,Wei Duan,Hwee-Ling Koh,Shu-Feng Zhou +8 more
TL;DR: An extensive review of the literature identified reported herb-drug interactions with clinical significance, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined.
Journal ArticleDOI
Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice.
Akira Murakami,Takuji Tanaka,Ji Yoon Lee,Young-Joon Surh,Ha Won Kim,Kyuichi Kawabata,Yoshimasa Nakamura,Suratwadee Jiwajinda,Hajime Ohigashi +8 more
TL;DR: Zerumbone is a promising agent for the prevention of both tumor initiating and promoting processes, through induction of anti‐oxidative and phase II drug metabolizing enzymes as well as attenuation of proinflammatory signaling pathways.
Journal ArticleDOI
Increased constitutive c-Jun N-terminal kinase signaling in mice lacking glutathione S-transferase Pi.
Robert Elsby,Neil R. Kitteringham,Christopher E. Goldring,Cerys A. Lovatt,Mark Chamberlain,Colin J. Henderson,C. Roland Wolf,B. Kevin Park +7 more
TL;DR: The role of GSTP as a direct inhibitor of JNK in vivo is demonstrated but also its role in regulating the constitutive expression of specific downstream molecular targets of the JNK signaling pathway is demonstrated.
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Human melanocyte biology, toxicology, and pathology.
TL;DR: The human melanocytes of the skin, hair, eyes, inner ears, and covering of the brain provide physiologic functions important in organ development and maintenance and may involve pigmentation, sensory functions, autoimmunity, or malignancy.
References
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Journal ArticleDOI
Biological Oxidations and P450 Reactions
TL;DR: It is established that the CYP1B1 cDNA indeed encodes the P450 responsible for polycyclic aromatic hydrocarbon (PAH) metabolism from C3H10T1/2 cells, which is an important contributor to activation of PAHs, particularly in extra hepatic tissues that are susceptible to cancer.
Journal ArticleDOI
Effect of naturally occurring coumarins on the formation of epidermal DNA adducts and skin tumors induced by benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in SENCAR mice.
Yingna Cai,Heather E. Kleiner,Dennis A. Johnston,Adam Dubowski,Samantha Bostic,Wayne Ivie,John DiGiovanni +6 more
TL;DR: Imperatorin was an effective inhibitor of skin tumor initiation by DMBA and also inhibited complete carcinogenesis by this PAH and Imperatorin at a dose of 400 nmol dramatically decreased formation of covalent DNA adducts derived from both the anti and syn diol epoxides of DMBA.