Robert J. Mauthe
Lawrence Livermore National Laboratory
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Featured researches published by Robert J. Mauthe.
Mutation Research | 1997
Kenneth W. Turteltaub; Robert J. Mauthe; Karen H. Dingley; John S. Vogel; Christopher E. Frantz; R. Colin Garner; Nancy H. Shen
Heterocyclic amines, such as 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), are mutagenic/carcinogenic compounds formed during the cooking of protein-rich foods. Human exposure to MeIQx has been estimated to range from ng/person/day to a few microgram/person/day. In contrast, animal studies have been conducted at doses in excess of 10 mg/kg/day. In order to determine the relevance of high-dose animal data for human exposure, the dose-response curves for [14C]-MeIQx have been determined in rodents at low doses under both single-dose and chronic dosing regimens using the high sensitivity of accelerator mass spectrometry (AMS). To make a direct species comparison, rodent and human colonic MeIQx-DNA adduct levels have been compared following oral administration of [14C]-MeIQx. The results of these studies show: (1) total MeIQx levels are highest in the liver > kidney > pancreas > intestine > blood; (2) MeIQx levels in the liver plateau after 7 days of chronic feeding; (3) hepatic MeIQx-DNA adducts begin to plateau after 2-4 weeks and reach steady-state levels between 4 and 12 weeks on chronic exposures; (4) hepatic DNA adducts generally increase as a linear function of administered dose for a single-dose exposure and as a power function for chronic feeding over a dose range spanning 4 orders of magnitude; (5) human colon DNA adduct levels are approximately 10 times greater than in rodents at the same dose and time point following exposure; and (6) > or = 90% of the MeIQx-DNA adduct in both rodent and human colon appears to be the dG-C8-MeIQx adduct. These studies show that MeIQx is readily available to the tissues for both humans and rodents and that adduct levels are generally linear with administered dose except at high chronic doses where adduct levels begin to plateau slightly. This plateau indicates that linear extrapolation from high-dose studies probably underestimates the amount of DNA damage present in the tissues following low dose. Further, if adducts represent the biologically effective dose, these data show that human colon may be as sensitive to the genotoxic effects of MeIQx as rat liver. The significance of these endpoints to tumor response remains to be determined.
International Journal of Cancer | 1999
Robert J. Mauthe; Karen H. Dingley; Steven H. Leveson; Stewart P.H.T. Freeman; Robert J. Turesky; R. Colin Garner; Kenneth W. Turteltaub
[2‐14C]2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx) was administered orally (304 ng/kg body‐weight dose based upon an average 70‐kg‐body‐weight subject) to 5 human colon‐cancer patients (58 to 84 years old), as well as to F344 rats and B6C3F1 mice. Colon tissue was collected from the human subjects at surgery and from the rodents 3.5 to 6 hr after administration. Colon DNA‐adduct levels and tissue available doses were measured by accelerator mass spectrometry (AMS). The mean levels of MeIQx in the histologically normal colon tissue were not different among the human (97 ± 26 pg MeIQx/g), rat (133 ± 15 pg/g) or mouse (78 ± 10 pg/g) tissues; and no difference existed between the levels detected in human normal and tumor tissue (101 ± 15 pg/g). Mean DNA‐adduct levels in normal human colon (26 ± 4 adducts/1012 nucleotides) were significantly greater (p < 0.01) than in rats (17.1 ± 1 adduct/1012 nucleotides) or mice (20.6 ± 0.9 adduct/1012 nucleotides). No difference existed in adduct levels between normal and tumor tissue in humans. These results show that MeIQx forms DNA adducts in human colon at low dose, and that the human colon may be more sensitive to the effects of MeIQx than that of mice or rats. Int. J. Cancer 80:539–545, 1999.
Chemico-Biological Interactions | 1997
Ian N.H. White; Elizabeth A. Martin; Robert J. Mauthe; John S. Vogel; Kenneth W. Turteltaub; Lewis L. Smith
Tamoxifen, widely used as adjuvant therapy in the treatment of breast cancer, is now undergoing trials as a cancer chemopreventative agent. Previous work has shown an association between 32P-postlabelled adducts in rat liver DNA and the development of liver tumours. With the use of accelerator mass spectrometry, [14C]tamoxifen was shown to bind to liver DNA of female rats in a dose-dependent manner and was linear over 0.1-1 mg/kg, compatible with the therapeutic dose used in women (20 mg/person per day). Radiolabel could also be detected in extrahepatic organs, including reproductive and GI-tract, where levels were about 18 and 46%, respectively those seen in liver. Following enzymatic hydrolysis of liver DNA, normal nucleotides by HPLC showed < 2% incorporation of the [14C]radioactivity while > 80% appeared as non-polar products. In contrast, when animals were given an equivalent dose of [14C]toremifene, binding to DNA was an order of magnitude lower than that seen with tamoxifen and no evidence of non-polar adducted nucleotides following HPLC. However, in vitro, using human, rat or mouse liver microsomal preparations, NADPH-dependent binding of both toremifene and tamoxifen to calf thymus DNA could be demonstrated, suggesting that under favourable circumstances toremifene is capable of undergoing conversion to reactive intermediates.
Journal of Applied Toxicology | 1997
Bruce A. Buchholz; Norma H. Pawley; John S. Vogel; Robert J. Mauthe
We studied the effect of pyridostigmine bromide, a nerve agent prophylactic, on the central nervous system (CNS) uptake of [14C]permethrin, a pyrethroid insecticide, at scaled human‐equivalent exposures in rats using accelerator mass spectrometry (AMS). AMS detects 14C at attomole sensitivities and determines the tissue distribution of 14C‐labeled compounds. Pyridostigmine bromide in chow at 7.75 mg kg−1 per day lowered the CNS tissue levels of permethrin, dosed at 4.75 μg kg−1, in the CNS of rats by 30%. These results are inconsistent with hypothesized synergy of such compounds as a precursor to ‘Gulf War syndrome’.
Journal of Pharmaceutical and Biomedical Analysis | 1998
Robert J. Mauthe; E Sideras-Haddad; Kenneth W. Turteltaub; Graham Bench
We described the use of Nuclear microscopy (microbeam PIXE) for the quantitative micron scale analysis of platinum based chemotherapeutic agents in individual cell and tissue slices. We demonstrate that microbeam PIXE has the sensitivity and accuracy to quantitatively measure the uptake of the chemotherapeutic agent cis-diamminedichloroplatinum (II) (cisplatin) and monitor other endogenous metal contents in single cells in a time- and dose-dependent fashion. Additionally, the technique can quantitatively image therapeutic levels of cisplatin and cisplatin analogs including cis-diammine[1,1-cyclobutanedicarboxylato] platinum (II) (carboplatin) in tissues from an animal model. This quantitative imaging microscopy has general application for the sensitive measurement of metal containing drugs/compounds at the cellular level and allows the study of cellular distribution and mechanism of action related to toxic response and cell function.
Carcinogenesis | 1995
Robert J. Mauthe; Vanessa M. Cook; Stephanie L. Coffing; William M. Baird
Carcinogenesis | 1997
Elizabeth A. Martin; Philip Carthew; Ian N.H. White; Robert T. Heydon; Margaret Gaskell; Robert J. Mauthe; Kenneth W. Turteltaub; Lewis L. Smith
Journal of Pharmaceutical and Biomedical Analysis | 1997
Barry Kaye; R. Colin Garner; Robert J. Mauthe; Stewart P.H.T. Freeman; Kenneth W. Turteltaub
Carcinogenesis | 1998
Robert J. Mauthe; Elizabeth G. Snyderwine; Amit Ghoshal; Stewart P.H.T. Freeman; Kenneth W. Turteltaub
Cancer Research | 1996
Michael A. Malfatti; M. Suzanne Connors; Robert J. Mauthe; James S. Felton