PubMed Health⌕ Search

Biomedical subjects

D H Desai

Publications and source records attributed to D H Desai.

8 recordsLinked to original sources
PubMed1995

Enhancement of esophageal carcinogenesis in male F344 rats by dietary phenylhexyl isothiocyanate.

The purpose of this study was to evaluate the potential effects of dietary 6-phenylhexyl isothiocyanate (PHITC) on N-nitrosomethylbenzylamine (NMBA)-induced esophageal carcinogenesis in rats. Groups of 15 male F344 rats received weekly s.c. injections of NMBA in 20% dimethylsulfoxide or the vehicle alone for 15 consecutive weeks. Two weeks prior to initiation of carcinogen or vehicle injections rats were provided with modified AIN-76A diet or modified AIN-76A diet containing PHITC at levels of 0.4, 1.0 or 2.5 mumol/g diet. Experimental controls consisted of groups that received only the vehicle (vehicle controls), NMBA (carcinogen controls) or PHITC at the high dose level of 2.5 mumol/g diet. No esophageal tumors or preneoplastic lesions were detected in rats that received the vehicle or PHITC alone. In contrast, all rats treated with NMBA alone or PHITC + NMBA exhibited esophageal tumors and preneoplastic esophageal lesions. In groups that received PHITC + NMBA tumor multiplicity was increased by 21-69% when compared with rats treated with NMBA alone, indicating that PHITC enhanced esophageal tumorigenesis in this model system. These results, in conjunction with our previous work, demonstrate that arylalkyl isothiocyanates may inhibit or enhance esophageal tumorigenesis in the NMBA-treated rat. The ability of isothiocyanates to inhibit or enhance experimental tumorigenesis may depend on alkyl chain length of the isothiocyanate, the animal species examined and the specific carcinogen employed.

Animals↗
PubMed1994

Structure-activity relationships of isothiocyanates as mechanism-based inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice.

A structure-activity relationship study was carried out to identify structural features in arylalkyl and alkyl isothiocyanates that are associated with the inhibitory potency of these compounds against lung tumorigenesis induced in A/J mice by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These features include the alkyl chain length, phenyl substitution, and secondary isothiocyanates. The naturally occurring allyl isothiocyanate, phenethyl isothiocyanate, and the synthetic analogues such as 6-phenylhexyl isothiocyanate, 8-phenyloctyl isothiocyanate, 10-phenyldecyl isothiocyanate, 1,2-diphenylethyl isothiocyanate, 2,2-diphenylethyl isothiocyanate, and alkyl isothiocyanates (with 1-hexyl, 2-hexyl, and 1-dodecyl as alkyl moieties) were assayed in mice for their tumor inhibitory potential. The isothiocyanates were given in corn oil by gavage at doses of either 0.04, 0.1, and 0.2 mumol or 1 and 5 mumol 2 h prior to a single i.p. injection of 10 mumol NNK. Mice were sacrificed 16 weeks later and lung adenomas were counted. At 0.2 mumol, 8-phenyloctyl isothiocyanate and 10-phenyldecyl isothiocyanate were stronger inhibitors than the previously tested 6-phenylhexyl isothiocyanate, but the difference in potency was not obvious at the lower doses. At both 1 and 5 mumol, allyl isothiocyanate was inactive, while the other five synthetic isothiocyanates were considerably more potent than phenethyl isothiocyanate. In the alkyl isothiocyanate series, 2-hexyl isothiocyanate was more potent than 1-hexyl isothiocyanate, while 1-dodecyl isothiocyanate was the most potent at 1 mumol, reducing tumor multiplicity in the group treated with NNK alone from 11.1 to the background level. Also, 1,2-diphenylethyl isothiocyanate appeared to be a stronger inhibitor than 2,2-diphenylethyl isothiocyanate. In this study we have shown that the phenyl moiety is not essential for the inhibitory activity since alkyl isothiocyanates exhibit strong inhibitory effects against lung tumorigenesis. We have also shown that secondary isothiocyanates possess a higher potency than their structural isomers bearing a primary isothiocyanate. From results of this study and of seven previously studied isothiocyanates, we conclude that the observed inhibitory potency of isothiocyanates in the A/J mouse lung tumor model is correlated with their partition coefficients (log P) and the pseudo first order rate constants for the reaction of isothiocyanates toward glutathione (kobs). These results reveal that both high lipophilicity and low reactivity of isothiocyanates are important for inhibitory activity toward NNK-induced lung tumorigenesis. These observations provide a structural basis for the discovery of more effective chemopreventive agents.

Adenoma↗
PubMed1991

Structure-activity relationships for inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone lung tumorigenesis by arylalkyl isothiocyanates in A/J mice.

Phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), 4-phenylbutyl isothiocyanate (PBITC), and the newly synthesized 5-phenylpentyl isothiocyanate (PPeITC), 6-phenylhexyl isothiocyanate (PHITC), and 4-(3-pyridyl)butyl isothiocyanate (PyBITC) were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the lungs of A/J mice. Mice were administered isothiocyanates by gavage for 4 consecutive days at doses of 5, 1, or 0.2 mumol/day prior to administration of 10 mumol of NNK by i.p. injection. Mice were sacrificed 16 weeks after NNK administration and pulmonary adenomas were quantitated, PEITC effectively inhibited NNK-induced lung tumors at a dose of 5 mumol/day but was not inhibitory at doses of 1 or 0.2 mumol/day. PPITC, PBITC, PPeITC, and PHITC were all considerably more potent inhibitors of NNK lung tumorigenesis than PEITC. While virtually no differences in inhibitory activity could be ascertained for PPITC, PBITC, and PPeITC, PHITC appeared to be the most potent tumor inhibitor of all of the compounds. At a dose of 0.2 mumol/day, PHITC pretreatment reduced tumor multiplicity by 85%. PyBITC, an analogue of both NNK and PBITC, was ineffective as an inhibitor. Using the same protocol, the compounds were found to have qualitatively similar inhibitory effects on NNK-induced DNA methylation when administered at 1 mumol/day. These results extend our previous findings that increased alkyl chain length enhances the inhibitory activity of an arylalkyl isothiocyanate toward NNK lung tumorigenesis and demonstrate the exceptional chemopreventive potentials of two new isothiocyanates, PPeITC and PHITC.

Animals↗
PubMedDate not supplied

Synthesis of a hapten to be used in development of immunoassays for trans-3'-hydroxycotinine, a major metabolite of cotinine.

4-Carboxyl-substituted analogues of trans-3'-hydroxycotinine were synthesized to be covalently linked to macromolecules for antibody production. 3-Pyridyl-N-methylnitrone was condensed with dimethyl fumarate to give two isomeric isoxazolidines. Hydrogenolysis of the major product [2RS-(2 alpha,3 alpha,3 beta)]-3-carbomethoxy-3- [[(benzyloxy)carbonyl]oxy]-1-methyl-5-oxo-2-(3-pyridinyl)pyrrolidine with Pd/C followed by hydrolysis gave [2RS-(2 alpha,3 beta,4 beta)]-4-hydroxy-1-methyl-5-oxo-2-(3-pyridinyl)-3- pyrrolidinecarboxylic acid. The same compound was also prepared in two steps in high yield starting with dibenzyl fumarate and 3-pyridyl-N-methylnitrone.

Cotinine↗
PubMedDate not supplied

Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone pulmonary metabolism and tumorigenicity in mice by analogues of the investigational chemotherapeutic drug 4-ipomeanol.

4-Ipomeanol (IPO) is an investigational chemotherapeutic drug with specific toxicity toward the lung. It is metabolically activated to reactive intermediates by cytochrome P450 enzymes present in Clara cells. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a highly carcinogenic tobacco-specific nitrosamine with organo-specificity for the lung. Like IPO, which it resembles structurally, it is metabolically activated by cytochrome P450 enzymes of rat Clara cells. We synthesized nontoxic analogues of IPO and tested their activities as inhibitors of the metabolism and tumorigenicity of NNK. The IPO analogues synthesized were 4-hydroxy-1-phenyl-1-pentanone (HPP), 7-hydroxy-1-phenyl-1-octanone (HPO), 4-hydroxy-1-(2-thienyl)-1-pentanone (HTP), and 4-hydroxy-1-(3-pyridyl)-1-pentanone (HPYP). When added to A/J mouse lung microsomal incubations, all compounds significantly inhibited the oxidative pathways of NNK metabolism--alpha-hydroxylation and pyridine N-oxidation--to varying extents. Inhibition of carbonyl reduction of NNK was generally less effective. Inhibition of alpha-hydroxylation by IPO, HPP, and HTP was more pronounced in incubations with lung microsomes than with liver microsomes. None of the IPO analogues showed significant toxicity when given to A/J mice at a dose of 25 mumol; IPO itself was lethal at this dose. HPP and HPO, at doses of 25 mumol, significantly inhibited lung tumor multiplicity in mice treated with NNK; the other analogues and IPO itself were ineffective. The results of this study provide new leads for development of inhibitors of NNK metabolism and chemical probes for the active site of P450 enzymes in Clara cells.

Animals↗