Split hand/split foot malformation with hearing loss: first report of families linked to the SHFM1 locus in 7q21.

Developmental anomalies of the appendicular skeleton are among the most common and easily ascertained birth defects. Split hand/split foot malformations, distinctive in having deficiency of the central rays, occur as isolated anomalies and as one component of multisystem syndromes. The clinical and molecular characterization of a new syndrome, found in two unrelated families, consisting of split foot with hearing loss, is presented here. As in other split hand/split foot conditions, variable expression and reduced penetrance is notable. In the larger family, variably expressed split foot malformations were found in 6 of 11 gene carriers. and mild-to-moderate sensorineural hearing loss in 4. Split hand and cleft lip/palate in one individual and tibial deficiency in another suggest that these malformations are uncommon components of the syndrome. Ectodermal abnormalities did not occur. In the second family, variable split foot was observed in 3 of 4 gene carriers, and sensorineural deafness was present in 3. Split hand was only seen in a gene carrier who also had split foot and deafness. One gene carrier only had deafness. The gene for split hand split foot with sensorineural hearing loss was linked to markers in 7q21 in both families, with a combined (maximum LOD score of 4.37 at theta = 0.0 for locus D7S527) at 80% penetrance. Efforts to identify the responsible gene have not yet been successful.

Inhibition of metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by limonene.

Previous work by others shows that d-limonene (LIM) inhibits carcinogen-induced lung tumorigenesis in mice and strongly suggests that LIM can inhibit the metabolic activation of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Thus, in the current study, the ability of LIM and other monoterpenes to inhibit the activation of the tobacco-specific NNK was examined in murine pulmonary and hepatic microsomes after addition in vitro or administration in vivo. LIM inhibited the metabolic activation of NNK in both pulmonary and hepatic microsomes. Perillyl alcohol was a more potent inhibitor than LIM, while p-menth-1-ene was equipotent with LIM. After administration of LIM, limonene 1,2-oxide, or perillyl alcohol in vivo, significant inhibition of cytochrome P450-mediated metabolites (NNK N-oxide and HPB) was found at 1 and 4 h after administration of monoterpene. These results indicate that LIM and other monoterpenes are effective inhibitors of NNK metabolic activation, and that other monoterpenes such as perillyl alcohol may be effective chemopreventive agents against NNK-induced lung tumorigenesis.

Inhibition of metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by dietary benzaldehydes.

As part of a routine screening assay, benzaldehyde was found to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism. Consequently, the effects of benzaldehyde and several structurally related compounds on NNK metabolism were examined in murine hepatic and pulmonary microsomes. All test compounds inhibited formation of the metabolites 4-oxo-4-(3-pyridyl)butyric acid (OPBA), 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in hepatic microsomes and inhibited formation of 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK N-oxide), HPB, and NNAL in pulmonary microsomes. m-Anisaldehyde was the most potent inhibitor, and p-hydroxybenzaldehyde and syringaldehyde were less potent than benzaldehyde and vanillin in inhibiting the formation of OPBA and HPB, NNK metabolites that reflect metabolic activation (alpha-hydroxylation). Vanillin was essentially as potent as benzaldehyde. The mechanism of inhibition exhibited by these compounds appears to be competitive in nature. The ability of these compounds to inhibit NNK activation suggests that these compounds may be effective blocking agents (anti-initiating agents) for NNK lung tumorigenesis.

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.